ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.379A>G (p.Ile127Val)

dbSNP: rs121918089
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506089 SCV000605507 likely pathogenic not specified 2017-03-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000014392 SCV000696632 pathogenic Familial amyloid neuropathy 2016-02-26 criteria provided, single submitter clinical testing Variant summary: The TTR c.379A>G variant affects a conserved nucleotide, resulting in amino acid change from Ile to Val. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). However, functional studies indicate that TTRI107V dimers and tetramers decreased stability compared to controls. This variant is not found in 121416 control chromosomes, but has been cited in numerous ATTR patients from various ethnicities. Taken together, this is a disease variant and was classified as pathogenic.
Invitae RCV000014392 SCV000769146 pathogenic Familial amyloid neuropathy 2023-12-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 127 of the TTR protein (p.Ile127Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyloidosis (PMID: 7914929, 8081397, 9748014, 20209591, 24101130, 26537620, 27025994, 27066555). This variant is also known as p.Ile107Val. ClinVar contains an entry for this variant (Variation ID: 13450). 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: 17503405). This variant disrupts the p.Ile127 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 22745357, 24480837), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000014392 SCV001140874 pathogenic Familial amyloid neuropathy 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001090344 SCV001245843 likely pathogenic not provided 2023-10-01 criteria provided, single submitter clinical testing TTR: PM2, PM5, PS3:Moderate, PS4:Supporting
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001090344 SCV001446722 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001090344 SCV001476395 pathogenic not provided 2023-07-21 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In some published literature, this variant is referred to as p.Ile107Val.
GeneDx RCV001090344 SCV002588084 pathogenic not provided 2022-10-26 criteria provided, single submitter clinical testing Published functional studies demonstrate that TTR dimers from individuals heterozygous for TTRI127V are less stable than dimers from wild type individuals (Atland K et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as I107V; This variant is associated with the following publications: (PMID: 22301727, 8081397, 30306720, 20209591, 22745357, 19781421, 12039669, 7914929, 24101130, 32723050, 33481097, 33188503, 33844361, 34668655, 34602081, 34746851, 33283548, 34391735, 35665045, 35599006, 35417510, 35346209, 35331287, ScirpaR2022, 17443043, 9748014, 27025994, 27066555, 34658264, 26537620, 29520877, 26656838, 34440326, 35637921, 35580748, 17503405)
Ambry Genetics RCV002354161 SCV002622727 pathogenic Cardiovascular phenotype 2023-12-08 criteria provided, single submitter clinical testing The c.379A>G (p.I127V) alteration is located in exon 4 (coding exon 4) of the TTR gene. This alteration results from a A to G substitution at nucleotide position 379, causing the isoleucine (I) at amino acid position 127 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the TTR c.379A>G alteration was not observed with coverage at this location. This variant, historically known as p.I107V, has been detected in multiple individuals with TTR-related amyloidosis (Jacobson, 1994; Planté-Bordeneuve, 1998; Damy, 2016; Kuzume, 2016). Two different alterations located at the same amino acid position, p.I127F (c.379A>T, historically known as p.I107F) and p.I127M (c.381T>G, historically known as p.I107M), have also been detected in individuals with TTR-related amyloidosis (Cappellari, 2011; Lv, 2014). This amino acid is highly conserved in available vertebrate species. Functional studies indicate that this variant results in unstable interaction between transthyretin tetramers (Altland, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002504784 SCV002813237 pathogenic Hyperthyroxinemia, dystransthyretinemic; Familial amyloid neuropathy; Carpal tunnel syndrome 1 2021-09-09 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV003458163 SCV004183383 pathogenic Hereditary amyloidosis 2022-02-22 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 strong, PS4 strong, PM2 moderated
OMIM RCV000014392 SCV000034641 pathogenic Familial amyloid neuropathy 1994-05-01 no assertion criteria provided literature only

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