rs76992529
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PM1PM5PP5_Very_StrongBP4BS1_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
Consequence
NM_000371.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
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 0.00467 AC: 710AN: 152112Hom.: 5 Cov.: 33
GnomAD3 exomes AF: 0.00113 AC: 283AN: 251408Hom.: 1 AF XY: 0.000670 AC XY: 91AN XY: 135884
GnomAD4 exome AF: 0.000494 AC: 722AN: 1461852Hom.: 3 Cov.: 31 AF XY: 0.000432 AC XY: 314AN XY: 727234
GnomAD4 genome 0.00467 AC: 711AN: 152230Hom.: 5 Cov.: 33 AF XY: 0.00421 AC XY: 313AN XY: 74432
ClinVar
Submissions by phenotype
Amyloidosis, hereditary systemic 1 Pathogenic:20Other:1
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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. -
The p.Val142Ile variant in the TTR gene, also referred to as V122I, is one of the most common pathogenic variants associated with hereditary transthyretin amyloidosis and is predominantly identified in individuals of African descent (Jacobson et al., 1997; Yamashita et al., 2005; Sekijima, 2021). This variant is associated with cardiac amyloidosis typically presenting as restrictive cardiomyopathy in the 7- 8th decade of life. The true penetrance of p.Val142Ile is unknown; however, this variant is associated with increased rates of heart failure and lower overall survival (Buxbaum et al., 2010; Chandrashekar et al., 2021; Kozlitina et al., 2022). Individuals who are homozygous for p.Val142Ile manifest symptoms at an earlier age than heterozygotes (Reddi et al., 2014). This variant has been identified in 405/24,968 African/African American chromosomes (435/282,792 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 13426). Multiple functional studies have demonstrated that this variant results in reduced tetramer stability and increased amyloid fibril formation (Jiang et al., 2001; Askanas et al., 2003). Computational tools predict that the p.Val142Ile variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Val142Ile variant as pathogenic for autosomal dominant hereditary transthyretin amyloidosis based on the information above. [ACMG evidence codes used: PS3; PS4; PP3] -
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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. -
ACMG Criteria: PS3, PS4, PM5_P, PP3, PP5; Variant was found in heterozygous state. -
This variant is also known as (p.Val122Ile) by legacy nomenclature. This is a known Pathogenic variant that has been previously reported as a heterozygous change in patients with a cardiac amyloidosis phenotype of hereditary transthyretin amyloidosis (PMID: 22745357, 24184229, 25846356, 24070600, 20301373). Functional studies demonstrated an altered speed of tetramer dissociation, greater formation of amyloid fibrils, and an unstable TTR tetramer compared to wild type (PMID: 11752443, 18276611). The c.424G>A (p.Val142Ile) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.09% (1433/1614082), including 8 homozygous individuals. Based on the available evidence, c.424G>A (p.Val142Ile) is classified as Pathogenic. -
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. -
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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. -
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. -
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. -
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. -
ACMG classification criteria: PS3 strong, PS4 strong, PP1 strong -
The TTR c.424G>A p.(Val142Ile) missense variant, also referred to as p.(Val122Ile), has been described as one of the most common pathogenic variants associated with hereditary transthyretin amyloidosis (PMID: 20301373; 26123279). The p.(Val142Ile) variant is generally associated with cardiac amyloidosis with either limited or no significant neurological involvement (PMID: 20435197; 24184229; 25551524; 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; 27386769; 27838833; 31135624; 33467513). Phenotype severity generally increases after the age of 60 and can include congestive heart failure. Penetrance is incomplete and variable by ethnic origin and geographic region (PMID: 20301373). The highest frequency of this allele in the Genome Aggregation Database is 0.01697 in the African/African American population (version 4.0.0). This allele frequency is high but is consistent with disease prevalence estimates in specific populations. Based on the available evidence, the c.424G>A p.(Val142Ile) variant is classified as pathogenic for hereditary transthyretin amyloidosis. -
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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 -
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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. -
not provided Pathogenic:17
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) -
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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. -
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TTR: PP1:Strong, PS4, PS3:Moderate -
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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) -
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Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 Pathogenic:2
PS3+PS4+PP4 -
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TTR-related disorder Pathogenic:2
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. -
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. -
Charcot-Marie-Tooth disease Pathogenic:1
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Cardiomyopathy Pathogenic:1
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Tip-toe gait Pathogenic:1
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ATTRV122I amyloidosis Pathogenic:1
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
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
PS4,PS3,PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at