rs28933979

Positions:

• chr18-31592974-G-A
• chr18-31592974-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_000371.4(TTR):​c.148G>A​(p.Val50Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V50A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:33 O:1
• Conservation: PhyloP100: 2.83

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a strand (size 6) in uniprot entity TTHY_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000371.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31592975-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant 18-31592974-G-A is Pathogenic according to our data. Variant chr18-31592974-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592974-G-A is described in Lovd as [Pathogenic]. Variant chr18-31592974-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.148G>A	p.Val50Met	missense_variant	2/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.148G>A	p.Val50Met	missense_variant	2/4	1	NM_000371.4	ENSP00000237014	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251462 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000581 AC: 85 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000644 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:33 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:17

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 13, 2023	Val50Met is the most common variant associated with TTR-related hereditary amyloidosis; 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 has also been reported in patients with cardiac involvement with and without neuropathy (PMID: 19808383, 20209591, 23993291). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. This variant is also referred to as Val30Met in published literature. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed this variant caused reduced stability of the protein (PMID: 17503405, 15820680). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 04, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The TTR c.148G>A; p.Val50Met variant (rs28933979), also known as Val30Met, is the most common pathogenic TTR variant associated with familial amyloidotic polyneuropathy worldwide (Parman 2016). The variant has a variable clinical presentation ranging from asymptomatic carriers to systemic disease, having early-late onset disease subtypes (Arvidsson 2015, Beirao 2015, Coelho 2017, Parman 2016). Functional studies suggest the variant refolds from monomers to tetramers at a slower rate compared to wildtype (Jesus 2016), has decreased stability in the folded state (Altland 2007), and impairs the inflammatory response necessary for nerve regeneration (Goncalves 2014). This variant is reported as pathogenic in ClinVar (Variation ID: 13417), and observed in the general population with an overall allele frequency of 0.01% (25/246236 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.711). Additionally, other variants at this codon (p.Val50Ala, p.Val50Leu) have been reported in individuals with amyloid neuropathy and are considered pathogenic (Altland 2007, Suhr 2009). Based on available information, the p.Val50Met 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. Arvidsson S et al. Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition. PLoS One. 2015 Nov 23;10(11):e0143456. PMID: 26600306. Beirao JM et al. Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases. Amyloid. 2015;22(2):117-22. PMID: 26096568. Coelho T et al. Clinical measures in transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2017 Mar;55(3):323-332. PMID: 27422379. Goncalves NP et al. The inflammatory response to sciatic nerve injury in a familial amyloidotic polyneuropathy mouse model. Exp Neurol. 2014 Jul;257:76-87. PMID: 24800914. Jesus CS et al. A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation. Int J Mol Sci. 2016 Aug 31;17(9). PMID: 27589730. Parman Y et al. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol. 2016 Feb;29 Suppl 1:S3-S13. PMID: 26734951. Suhr OB et al. Report of five rare or previously unknown amyloidogenic transthyretin mutations disclosed in Sweden. Amyloid. 2009 Dec;16(4):208-14. PMID: 19922332. -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 20, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val30Met (aka p.Val50Met) in TTR. This variant has been seen in dozens of families with transthyretin-related amyloidosis. It is one of the most common disease-causing variants in TTR. This variant has been reported in association with autonomic neuropathy, ocular problems, leptomeningeal features, and polyneuropathy. Cardiomyopathy and nephropathy can be late stage manifestations. It has been observed in Portugal, Sweden, Japan, and the US. Age of onset is variable with this variant ranging from 17 to 80 years old. In endemic areas of Japan average onset is 40yo while in other areas of Japan it is 63 years. Individuals of Portugese ancestry have an average onset of 34 years. Individuals of Swedish, French, or British ancestry with this variant have a much later onset. Three other variants at this same codon have been associated with amyloidosis including p.Val30Ala, p.Val30Gly, p.Val30Leu. There is no variation at codon 30 list in the NHLBI exome sequencing project, which currently includes data on ~6500 Caucasian and African American individuals (as of November 16th, 2012). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as V30M; This variant is associated with the following publications: (PMID: 24455802, 24164154, 15820680, 18276611, 19602727, 26521788, 28475415, 29540472, 26513367, 28635949, 30811423, 18925456, 24555660, 23387326, 23993291, 22531659, 23080516, 17503405, 24800914, 24474780, 26115039, 27589730, 26104852, 27793437, 6736244, 18606975, 26096568, 19808383, 22382560, 26017327, 22620962, 24601850, 23833285, 22745357, 25525159, 25550818, 26115788, 19364362, 24046394, 20209591, 24101130, 22592564, 30243104, 30019395, 30213731, 31343348, 31371117, 30572722, 31718691, 29520877, 31919945, 32269295, 31589614, 32674397, 32399692, 32880476, 35142241, 35903975, 35945697, 35358243, 34980537, 35893595, 20301373, 33739616, 33373035, 32528171, 3479441, 34440326, 31701603, 32852783, 11523162, 32893242, 3762958, 18506713, 26587769, 32376792, 33726816, 34024775, 24395461, 3229002, 34059423, 34461735, 26537620, 26600212, 34658264, 35751086, 36228827, 37273706) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TTR: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PS3:Supporting -

Amyloidosis, hereditary systemic 1 Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.148G>A;p.(Val50Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 13417; PMID: 25550818; 15820680; 24601850; 22745357; 17503405; 30328212; 26088020; 20301373; OMIM: 176300.0001) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 25519307, 26088020) - .PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Transthyretin domain) - PM1. The variant is present at low allele frequencies population databases (rs28933979– gnomAD 0.0004600%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (Clinvar ID: 13430; 13440; 13465) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 26115788) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 06, 2021	The p.Val50Met variant in TTR (also described as p.Val30Met in the literature) is a common variant in individuals with hereditary transthyretin amyloidosis (ATTR), especially in those of Portuguese, Swedish and Japanese ancestry. It has been reported in a multitude of affected individuals and segregated with disease in >100 affected individuals from >95 families, although >100 individuals who carry this variant were found to be asymptomatic, suggesting reduced penetrance (Coelho 1994 PMID: 8071954, Hattori 2003 PMID: 14986482, Hellman 2008 PMID: 18925456, Rapezzi 2012 PMID: 22745357, Bekircan-Kurt 2015 PMID: 26115788, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 13417) and has been identified in 0.017% (19/113746) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this frequency is high in the general population, it is consistent with reduced penetrance. Two mouse models showed amyloid deposition and an inflammatory response similar to human familial transthyretin amyloidosis, and in vitro functional studies provide some evidence that this variant impacts protein function by reducing conformational stability (Yi 1991 PMID: 1992765, Altland 2007 PMID: 17503405, Goncalves 2014 PMID: 24800914). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant transthyretin amyloidosis, with reduced penetrance. ACMG/AMP criteria applied: PS4, PP1_Strong, PS3. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 12, 2022	This TTR variant (rs28933979) is rare (<0.1%) in a large population dataset (gnomAD: 26/251462 total alleles; 0.01%; no homozygotes) and has been reported in ClinVar. This variant, c.148G>A (p.Val50Met), also described as p.Val30Met in the literature, is the most common pathogenic variant in individuals with familial transthyretin amyloidosis. Individuals with this variant have a variable clinical presentation ranging from asymptomatic carriers to systemic disease, consistent with reduced penetrance. Other pathogenic variants at this same nucleotide position have been associated with amyloidosis, including c.148G>C (p.Val50Leu). Experimental studies demonstrate that this missense variant significantly affects protein stability. In addition, transgenic mice containing this variant showed amyloid deposition and an inflammatory response similar to human familial transthyretin amyloidosis. This variant was also reported in the patient's symptomatic father, who was tested by an outside laboratory. We consider this variant to be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Mar 30, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 21, 2019	Across a selection of the available literature, the TTR c.148G>A (p.Val50Met) missense variant has been identified as the most common variant in individuals with familial transthyretin amyloidosis (ATTR), with an estimated frequency of 0.04 in affected individulas from Sweden. This variant, also referred to as p.Val30Met in the literature, has been reported in both a homozygous and a heterozygous state (Andres et al. 2018; Hellman et al. 2008; Sekijima 2018). The age of onset of disease for individuals carrying the variant differs between populations, with Portugese and Japanese carriers presenting with earlier onset at 33 years. Overall, the penetrance increased with age and was significantly higher when the variant was inherited from the mother than from the father (Hellman et al. 2008). The p.Val50Met variant is reported at a frequency of 0.000487 in the Other population of the Genome Aggregation Database. This allele frequency is high but may be consistent with reduced penetrance. Transgenic mice carrying the p.Val50Met variant show higher amyloid deposition in the gastrointestinal tract, renal glomeruli, myocardium, small vascular walls, and thyroid with advancing age, which is consistent with findings from patient autopsy reports (Yi et al. 1991). Goncalves et al. (2014) showed a higher TTR expression, tissue specific deposition in nerves, reduced inflammatory response, and impaired regenerative process in injured nerves of transgenic p.Val50Met mice compared to their wild type counterparts. Based on the collective evidence and application of the ACMG criteria, the p.Val50Met variant is classified as pathogenic for familial transthyretin amyloidosis. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 05-09-2019 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	Institute of Immunology and Genetics Kaiserslautern	Jun 14, 2024	ACMG Criteria: PP1, PP3, PP5, PM2_P, PM5, PS3; Variant was found in heterozygous state -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 11, 2024	The variant is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org) dataset (total allele frequency: 0.010%). 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:25519307, 26088020). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013417). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID:26115788). Different missense changes at the same codon (p.Val50Ala, p.Val50Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013430, VCV000013440). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces valine with methionine at codon 50 of the TTR protein (p.Val50Met). There is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs28933979, gnomAD 0.02%). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 22620962, 22745357, 23833285, 24455802, 24555660, 26115788). It is commonly reported in individuals of Portuguese, Swedish and Japanese ancestry (PMID: 22620962, 23833285, 24555660). This variant is also known as p.Val30Met. ClinVar contains an entry for this variant (Variation ID: 13417). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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, 23080516, 24601850, 25550818). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 30, 2023

- -

TTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The TTR c.148G>A variant is predicted to result in the amino acid substitution p.Val50Met. This variant, also reported as p.Val30Met using legacy nomenclature, has been reported as one of the most common causative variants for hereditary transthyretin amyloidosis with individuals typically presenting with familial amyloidotic polyneuropathy/TTR-FAP (Ando et al. 2013. PubMed ID: 23425518; Saraiva et al. 1984. PubMed ID: 6736244; Holmgren et al. 1994. PubMed ID: 8064809; Skrahina et al. 2021. PubMed ID: 34658264). Penetrance for this variant is incomplete and increases with age (Hellman et al. 2008. PubMed ID: 18925456). Functional studies found this variant disrupts protein function (Altland et al. 2007. PubMed ID: 17503405; Jesus et al. 2016. PubMed ID: 27589730). This variant is reported in 0.017% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has also been consistently interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13417/). Additionally, alternate missense variants affecting the same amino acid (p.Val50Leu, p.Val50Ala, p.Val50Gly) have been reported in individuals with hereditary transthyretin amyloidosis (Murakami et al. 1992. PubMed ID: 1520326; Altland et al. 2007. PubMed ID: 17503405; Zeldenrust et al. 2012. PubMed ID: 22620962). This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 26, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.148G>A (p.V50M) alteration is located in exon 2 (coding exon 2) of the TTR gene. This alteration results from a G to A substitution at nucleotide position 148, causing the valine (V) at amino acid position 50 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (26/251462) total alleles studied. The highest observed frequency was 0.049% (3/6140) of Other alleles. This mutation was first reported in TTR-related amyloid protein of tissue samples from Portuguese individuals with familial amyloidotic polyneuropathy (Saraiva, 1984). This mutation has been detected in numerous individuals with hereditary transthyretin amyloidosis and is reported to be the most common TTR mutation; it is associated with the polyneuropathy type of familial TTR amyloidosis, but age of onset and severity are considered variable (Soares, 2004; Du, 2021; Andrés, 2018). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	.;N;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.025	.;D;.;.
Sift4G	Uncertain	0.0090	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.70, 0.75, 0.84
MVP		0.99
MPC		1.3
ClinPred		0.60	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.97

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: rs28933979; hg19: chr18-29172937;