rs76992529

Variant names:

• chr18-31598655-G-A
• rs76992529
• NM_000371.4:c.424G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PM1 PM5 PP5_Very_Strong BP4 BS1_Supporting

The NM_000371.4(TTR):​c.424G>A​(p.Val142Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000888 in 1,614,082 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V142A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:46 O:1
• Conservation: PhyloP100: 3.22

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) in NM_000371.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant 18-31598655-G-A is Pathogenic according to our data. Variant chr18-31598655-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31598655-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.009103388). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00467 (711/152230) while in subpopulation AFR AF= 0.0165 (687/41538). AF 95% confidence interval is 0.0155. There are 5 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.424G>A	p.Val142Ile	missense_variant	Exon 4 of 4	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-2960C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.424G>A	p.Val142Ile	missense_variant	Exon 4 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.424G>A	p.Val142Ile	missense_variant	Exon 6 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.328G>A	p.Val110Ile	missense_variant	Exon 4 of 4	5		ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 710 AN: 152112 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00113 AC: 283 AN: 251408 Hom.: 1 AF XY: 0.000670 AC XY: 91 AN XY: 135884

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461852 Hom.: 3 Cov.: 31 AF XY: 0.000432 AC XY: 314 AN XY: 727234

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152230 Hom.: 5 Cov.: 33 AF XY: 0.00421 AC XY: 313 AN XY: 74432

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00110 Hom.: 3

Bravo AF: 0.00560

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 167

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:46 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:19 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2020	The p.Val142Ile variant in TTR (alternate nomenclature p.Val122Ile) has been reported in >70 predominantly African American individuals with confirmed cardiac amyloidosis that presented with clinical features of cardiomyopathy or heart failure that typically presented with a later onset (after age 60-70). It is believed to be the most common variant identified, particularly amongst elderly African Americans (Jacobson 1997, Conners 2009, Lee 2011, Ruberg 2012, Arruda-Olsen 2013, Damy 2016). Individuals homozygous for the variant have been reported to have earlier onset of symptoms (Reddi 2014, Liu 2014). This variant has been shown to increase the risk for congestive heart failure in older individuals (>70 years), with two small studies reporting an age adjusted odds ratio of 1.5-2 [95% CI 1.2-2.7] (Quarta 2015, Damrauer 2019). Additionally, this variant has also been reported as a pathogenic variant by several clinical laboratories in ClinVar (Variation ID 13426). It is present in 1.6% (405/24968) of African chromosomes by gnomAD, including 3 homozygotes. Although this frequency is high in the general population, it is consistent with the age-dependent and possibly reduced penetrance of this disease. This variant has been shown to render the TTR protein complex unstable, causing misfolding and deposits in the myocardium (Jiang 2001, Askansas 2003). In summary, this variant is pathogenic for autosomal dominant late-onset transthyretin amyloidosis, though penetrance may not be complete. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.424G>A;p.(Val142Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13426; OMIM: 176300.0009; PMID: 12874414; PMID: 25551524; PMID: 30938420; PMID: 31359320; PMID: 27720586; PMID: 26123279; PMID:11752443) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 12874414, 27758856, 27720586, 11752443) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (TR_THY domain) - PM1. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 23, 2022	The c.424G>A variant in TTR is an established pathogenic variant in individuals of African American ancestry with hereditary transthyretin (ATTR) amyloidosis related cardiomyopathy as it has been reported in 10% of African Americans older than age 65 with severe congestive heart failure [PMID: 28102864], and it has been deposited in ClinVar [ClinVar ID: 13426] as Pathogenic for hereditary transthyretin amyloidosis related cardiomyopathy by multiple submitters. The c.424G>A variant is observed almost exclusively in individuals of African American ancestry (~1.5% minor allele frequency) in population databases (gnomAD v2.1.1 and v3.1.2), suggesting it being a founder mutation for this population. The c.424G>A variant is located in the exon 4 of this 4-exon gene and replaces an evolutionarily conserved valine amino acid with isoleucine at position 142 of the encoded protein (p.Val142Ile) (also known as p.Val122Ile based on nomenclature for the circulating protein after N-terminal peptide cleavage) [PMIDs: 2646319, 2349941]. Functional studies demonstrated that the p.(Val142Ile) variant confer amyloidogenic properties via causing conformational changes and reducing the stability of the physiologic TTR tetramer [PMIDs: 17503405, 18276611]. Based on available evidence this c.424G>A p.Val142Ile variant identified in TTR is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 17, 2023	The TTR c.424G>A (p.Val142Ile) missense variant results in the substitution of valine at amino acid position at 142 with isoleucine. This variant, which is also known as p.Val122Ile, has been described as one of the most common pathogenic variants associated with hereditary transthyretin amyloidosis and is present in a heterozygous state at a frequency of approximately 3.5% in the African American population (PMID: 20301373; PMID: 26123279). The c.424G>A variant is generally associated with cardiac amyloidosis with either limited or no significant neurological involvement (PMID: 20435197; PMID: 24184229; PMID: 25551524; PMID: 26537620). However, additional phenotypes have been observed which include gait abnormalities, gastrointestinal and urinary phenotypes, muscle weakness, carpal tunnel syndrome, spinal stenosis, and neurologic features including tingling, numbness, and neuropathic pain (PMID: 25819286; PMID: 27386769; PMID: 27838833; PMID: 31135624; PMID: 33467513). Phenotype severity generally increases after the age of 60 and can include congestive heart failure (PMID: 20435197; PMID: 24184229; PMID: 25551524; PMID: 26537620). Penetrance is incomplete and variable by ethnic origin and geographic region (PMID: 20301373). While hereditary transthyretin amyloidosis is inherited in an autosomal dominant pattern, homozygous and compound heterozygous individuals are also reported: across a selection of the available literature, the c.424G>A variant is found in a homozygous state in 19 patients, in a compound heterozygous state in two patients, and in a heterozygous state in 36 patients (PMID: 2349941; PMID: 9017939; PMID: 20435197; PMID: 24073013; PMID: 24184229; PMID: 24633258; PMID: 25819286; PMID: 25551524; PMID: 26537620; PMID: 26428663). The highest frequency of this allele in the Genome Aggregation Database is 0.01654 in the African/African American population (version 3.1.2). This allele frequency is high but is consistent with disease prevalence estimates in specific populations. Functional studies showed that the variant demonstrated an altered speed of tetramer dissociation, greater formation of amyloid fibrils, and an unstable TTR tetramer compared to wild type (PMID: 11752443; PMID: 18276611). Based on the available evidence, the c.424G>A (p.Val142Ile) variant is classified as pathogenic for hereditary transthyretin amyloidosis. -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Feb 09, 2024	The TTR c.424G>A (p.Val142Ile) variant, also known as Val122Ile, has been reported in many individuals of predominantly African American ancestry affected with cardiac amyloidosis and late onset cardiomyopathy or congestive heart failure and has been shown to have an age-adjusted odds ratio of 1.5-2 [95% CI 1.2-2.7] (Damrauer SM et al., PMID: 31821430; Dungu JN et al., PMID: 27618855; Jacobson DR et al., PMID: 27652282; Quarta CC et al., PMID: 25551524; Reddi HV et al., PMID: 24184229). This variant has been reported in the ClinVar database as a germline pathogenic variant by several submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.6% in the African/African American population, which is consistent with a reduced penetrance and age-dependent variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to transthyretin function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 06-01-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). The c.424G>A (p.Val142Ile) variant is present in the gnomAD population database at a frequency of 0.15% (417/277140) in the heterozygous state and a frequency of 0.001% (3/282792) in the homozygous state. The c.424G>A (p.Val142Ile) variant is found in approximately 3.5% of individuals with African American ancestry (PMID: 26123279, 34461737). This variant results in the cardiac amyloidosis phenotype (see Gene Information section for details on this specific phenotype) (PMID: 24070600, 24184229, 20435197, 22877808, 34461737). This variant has also been observed in individuals from other ancestries with a similar phenotype (PMID: 25846356, 22745357). Experimental studies have shown this variant weakens the stability of the TTR tetramer protein complexes (PMID: 15820680, 17503405, 18276611). The c.424G>A (p.Val142Ile) variant affects a weakly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.424G>A, p.Val142Ile variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	This sequence change replaces valine with isoleucine at codon 142 of the TTR protein (p.Val142Ile). There is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs76992529, gnomAD 1.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). It is commonly reported in individuals of African American ancestry (PMID: 20435197, 22745357, 22877808, 25846356). This variant is also known as p.Val122Ile. ClinVar contains an entry for this variant (Variation ID: 13426). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 17503405, 18276611). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Oct 12, 2022	ACMG Criteria: PS3, PS4, PM5_P, PP3, PP5; Variant was found in heterozygous state. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000371.3:c.424G>A (p.Val142Ile) was reported as Val122Ile in the TTR gene, and it has an allele frequency of 0.016 in African subpopulation in the gnomAD database. Functional studies demonstrate that Val122Ile affect TTR protein function (PMID: 18276611). V122I variant is the most common amyloidogenic mutation worldwide, associated with familial amyloidotic cardiomyopathy in individuals of African descent. It is estimated that 4% of African Americans are heterozygous for the V122I variant, with an age of onset at around 60 years of age (PMID: 18276611). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PS4; PP4; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	May 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 10, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Oct 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 16, 2022	ACMG classification criteria: PS3 strong, PS4 strong, PP1 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Variantyx, Inc.	Nov 07, 2022	This is a nonsynonymous variant in the TTR gene (OMIM 176300). Heterozygous pathogenic variants in this gene are associated with autosomal dominant hereditary transthyretin-related amyloidosis. This is an established founder variant in the African population, with an allele frequency of >3% in African Americans (PMID: 9017939, 26123279). It has been observed in individuals with transthyretin-related amyloidosis in both the homozygous and the heterozygous state (PMID: 25846356, 24184229, 12050338, 19781421, 22745357) (PS4). Functional studies have shown that this variant alters TTR protein function (PMID: 11752443, 12874414, 15820680, 17503405, 22184092, 24474780) (PS3). Multiple computational algorithms predict a deleterious effect for this substitution (PP3). This variant has a 1.654% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on current evidence, this variant is classified as pathogenic for autosomal dominant hereditary transthyretin-related amyloidosis. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	Feb 23, 2023	The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11752443). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013426). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11752443, 2349941, 25551524, 25819286, 26537620). Different missense changes at the same codon (p.Val142Ala, p.Val142Leu) have been reported to be associated with TTR related disorder (ClinVar ID: VCV001333466 / PMID: 10211412, 24101130 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:16

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	Originated in a small number of founder carriers in southern West Africa (Jacobson et al., 2016); Reported as heterozygous or homozygous in individuals with familial amyloid cardiomyopathy and senile systemic amyloidosis (SSA); these disorders usually have an age-dependent penetrance with onset later in life (age > 50-60 years), characterized by amyloid deposits in the heart leading to congestive heart failure and conduction system disturbances (Jacobson et al., 1997a; Jacobson et al., 1997b); Reported in individuals of varying ethnic backgrounds in the Online Registry for Mutations in Hereditary Amyloidosis (Rowczenio et al., 2014); Cultured skeletal muscle fibers from patients harboring the V142I variant had vacuolar degeneration, congophilic inclusions, clusters of immunocolocalizing beta-amyloid and TTR accumulations (Askanas et al., 2003); Renders the TTR complex unstable, leading to unfolding and lower tetramer stability (Jiang et al., 2001); This variant is associated with the following publications: (PMID: 18276611, 24474780, 22083004, 24633258, 27618855, 25997029, 26537620, 29520877, 31371117, 31821430, 20301373, 15820680, 17503405, 11752443, 12874414, 9017939, 25551524, 22995991, 23713495, 23716704, 22745357, 20435197, 24184229, 22184092, 24818650, 22877808, 20981092, 26894299, 26428663, 24070600, 2349941, 27652282, 28090011, 26243339, 27364045, 25819286, 26002815, 26123279, 27386769, 26017327, 28335735, 27838833, 28635949, 28944235, 29052438, 29073801, 28870641, 29016222, 30093168, 28475415, 29764897, 30683924, 31659433, 31740141, 31554435, 32674397, 32150461, 31980526, 31589614, 32269295, 26656838, 32399692, 32376792) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 24, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 12, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 26, 2024	The TTR c.424G>A; p.Val142Ile variant (rs76992529), also known as Val122Ile, is one of the most common pathogenic variants associated with late-onset amyloidosis in individuals often of African American ancestry (Buxbaum 2017, Damy 2016, Jacobson 2016) and is classified as pathogenic by several sources in the ClinVar database (Variation ID: 13426). The variant does not appear to have an effect on cardiac function until after the age of 60 (Buxbaum 2010, Reddi 2014, Quarta 2015). Although this variant commonly has a predominant clinical expression of hypertrophic restrictive cardiomyopathy with mild or no neurological symptoms, it has also been reported in an individual with neurological findings and no cardiac involvement (Stancanelli 2017). Functional studies have demonstrated instability of the variant tetramer protein (Altland 2007, Jiang 2001, Sekijima 2005, Steward 2008), and suggest the variant predisposes to accumulation of amyloid beta peptide as well as causes vacuolar degeneration leading to decreased viability of cultured skeletal muscle (Askanas 2003). This variant is found in the African/African American population with an allele frequency of 1.6% (405/24,968 alleles, including 3 homozygotes) in the Genome Aggregation Database. Although the allele frequency is high, it is consistent with the disease prevalence. The valine at codon 142 is highly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.645). Based on available information, this variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. PMID: 17503405. Askanas V et al. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003 Jul 22;61(2):257-60. PMID: 12874414. Buxbaum J et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010 May;159(5):864-70. PMID: 20435197. Buxbaum JN et al. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med. 2017 Jul;19(7):733-742. PMID: 28102864. Damy T et al. Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J. 2016 Jun 14;37(23):1826-34. PMID: 26537620. Jacobson DR et al. The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Mol Genet Genomic Med. 2016 Jul 14;4(5):548-56. PMID: 27652282. Jiang X et al. The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14943-8. PMID: 11752443. Reddi HV et al. Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life. J Mol Diagn. 2014 Jan;16(1):68-74. PMID: 24184229. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. PMID: 15820680. Stancanelli C et al. Phenotypic variability of TTR Val122Ile mutation: a Caucasian patient with axonal neuropathy and normal heart. Neurol Sci. 2017 Mar;38(3):525-526. PMID: 27838833. Steward RE et al. Different disease-causing mutations in transthyretin trigger the same conformational conversion. Protein Eng Des Sel. 2008 Mar;21(3):187-95. PMID: 18276611. Quarta CC et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 1;372(1):21-9. PMID: 25551524. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2023	This variant is the most common variant associated with autosomal dominant TTR-related amyloid cardiomyopathy (PMID: 9017939), formerly known as familial amyloidotic cardiomyopathy (FAC); therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. According to published literature, there is no significant difference in severity of clinical presentation between individuals with this variant in the heterozygous or homozygous state (PMID: 19781421); however, age of onset is reported to be earlier in homozygous individuals (PMID: 24184229, 28102864). This variant is also referred to as c.7356G>A (p.Val122Ile) in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11752443, 35903975) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TTR: PP1:Strong, PS4, PS3:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

TTR-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also known as p.Val122Ile by legacy nomenclature. The c.424G>A (p.Val142Ile) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.15% (435/282792) and in the homozygous state in three individuals. It is found in approximately 3.5% of African Americans (PMID: 26123279). This variant has been identified as a causative allele for late-onset cardiac amyloidosis; specifically, it is a common cause of amyloidosis in individuals of African American ancestry with affected individuals typically presenting after the sixth decade of life (PMID: 20435197, 22877808, 24070600, 24184229). This variant has also been observed in individuals from other ancestries with a similar amyloidosis phenotype (PMID: 25846356, 22745357). Experimental studies have shown that this variant weakens the stability of TTR tetramer protein complexes in plasma and cerebrospinal fluid (PMID: 15820680, 17503405, 18276611). Based on the available evidence, c.424G>A (p.Val142Ile) is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 13, 2024	The TTR c.424G>A variant is predicted to result in the amino acid substitution p.Val142Ile. This variant, also referred to as p.Val122Ile using legacy nomenclature, has been reported in many individuals with autosomal dominant hereditary amyloidosis and typically presents as familial amyloid cardiomyopathy (see, for example, Jacobson et al. 1990. PubMed ID: 2349941; Buxbaum et al. 2010. PubMed ID: 20435197; Dungu et al. 2016. PubMed ID: 27618855). Homozygotes have also been described (Dungu et al. 2016. PubMed ID: 27618855; Lopes et al. 2019. PubMed ID: 31554435). In vitro experimental studies indicate this variant impacts protein function (Jiang et al. 2001. PubMed ID: 11752443; Sekijma et al. 2005. PubMed ID: 15820680; Altland et al. 2007. PubMed ID: 17503405). It has been reported as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13426/). This variant is reported in 1.6% of alleles in individuals of African descent in gnomAD, including three homozygotes, which is consistent with variant being a founder event with high frequency in individuals of African descent (Jacobson et al. 1997. PubMed ID: 9017939; Jacobson et al. 2015. PubMed ID: 26123279). This variant is interpreted as pathogenic. -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PS3+PS4+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2024	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Anemia;C0030312:Pancytopenia;C1855710:Bone marrow hypocellularity Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 30, 2023

- -

Tip-toe gait Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Dec 19, 2022

- -

ATTRV122I amyloidosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Mar 12, 2019

This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.15% (417/277140), including three reports of hymozygous individuals. The p.Val142Ile is found in approximately 3.5% of African Americans. In silico analyses support a deleterious effect of the c.424G>A, p.Val142Ile variant on protein function. This variant is clearly defined as a late-onset cardiac amyloidosis causative allele (PMID: 24070600, 24184229). It is a common cause of amyloidosis in individuals of African American ancestry and typically causes symptoms after the sixth decade of life (PMID: 20435197, 22877808). It has also been observed in individuals from other populations and causes the same phenotype (PMID: 25846356, 22745357). ClinVar contains an entry for this variant (Variation ID: 13426). Experimental studies have shown that this missense change weakens the stability of the TTR tetramer protein complexes (PMID: 15820680, 17503405, 18276611). Based on the available evidence, the c.424G>A, p.Val142Ile variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2024

The c.424G>A (p.V142I) alteration (also known as p.V122I) is located in coding exon 4 of the TTR gene. This alteration results from a G to A substitution at nucleotide position 424, causing the valine (V) at amino acid position 142 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.154% (435/282792) total alleles studied. The highest observed frequency was 1.622% (405/24968) of African alleles. This alteration has been reported in multiple unrelated patients with amyloid polyneuropathy (Jacobson, 1990; Jacobson, 1997; Reddi, 2014; Jacobson, 2015; Swiecicki, 2015). This is the most common TTR mutation in individuals of African descent and is also associated with familial amyloidotic cardiomyopathy (Jacobson, 1997; Arvanitis, 2017). The clinical penetrance of this mutation is age-dependent; before age sixty-five, this mutation has little or no impact on cardiac function or mortality in the majority of patients, while after age seventy, heterozygotes show a higher frequency of congestive heart failure and greater mortality with more evidence of cardiac amyloidosis than age, gender, and ethnicity-matched controls (Buxbaum, 2010). This amino acid position is well conserved in available vertebrate species. Functional analysis demonstrated that the p.V142I alteration lowers the stability of the transthyretin tetramer and lowers the kinetic barrier for tetramer dissociation, which increases the extent and rate of amyloid fibril formation (Jiang, 2001). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Amyloidosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS4,PS3,PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;T;.
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	.;T;T;T
MetaRNN	Benign	0.0091	T;T;T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.0	M;M;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.48	.;N;.;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.023	.;D;.;.
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.27, 0.46, 0.80
MVP		0.94
MPC		0.39
ClinPred		0.065	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76992529; hg19: chr18-29178618; COSMIC: COSV99030963; COSMIC: COSV99030963;