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

dbSNP: rs121918089

Total submissions: 13

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	Amyloidosis, hereditary systemic 1	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014392	SCV000769146	pathogenic	Amyloidosis, hereditary systemic 1	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	Amyloidosis, hereditary systemic 1	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; Amyloidosis, hereditary systemic 1; 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
Mayo Clinic Laboratories, Mayo Clinic	RCV001090344	SCV005413291	pathogenic	not provided	2024-07-26	criteria provided, single submitter	clinical testing
OMIM	RCV000014392	SCV000034641	pathogenic	Amyloidosis, hereditary systemic 1	1994-05-01	no assertion criteria provided	literature only