Submissions for variant NM_000371.4(TTR):c.88T>C (p.Cys30Arg)

gnomAD frequency: 0.00001  dbSNP: rs121918083

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014386	SCV000696637	likely pathogenic	Familial amyloid neuropathy	2016-04-05	criteria provided, single submitter	clinical testing	Variant Summary: The c.88T>C variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a pathogenic outcome. The variant, also known as Cys10Arg, involves the only free Cysteine in TTR and is hypothesized to cause structural changes in the heterozygous TTR dimer and tetramer that lead to polymerization of TTR molecules (Uemichi_1992). The variant is absent from the large, broad ExAC control population. The variant was found in multiple affected individuals in the literature, including a family in which all tested affected males carried the variant while three unaffected females also carried the variant, suggesting some role of sex in the occurrence of disease (Uemichi_1992). One clinical lab has classified the variant as "pathogenic". Therefore, taken together, this variant has been classified as Likely Pathogenic.
Athena Diagnostics	RCV000993524	SCV001146566	uncertain significance	not provided	2018-09-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000993524	SCV001501203	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000014386	SCV001575268	pathogenic	Familial amyloid neuropathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 30 of the TTR protein (p.Cys30Arg). This variant is present in population databases (rs121918083, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1362222, 24664531; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Cys10Arg. ClinVar contains an entry for this variant (Variation ID: 13444). 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%. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000014386	SCV002580651	likely pathogenic	Familial amyloid neuropathy	2022-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298033	SCV003997335	uncertain significance	Cardiovascular phenotype	2023-06-06	criteria provided, single submitter	clinical testing	The p.C30R variant (also known as c.88T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 88. The cysteine at codon 30 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration, which is also known as p.C10R, has been reported in transthyretin (TTR) amyloidosis and related cardiomyopathy cohorts; however, clinical details were limited (Uemichi T et al. J Med Genet, 1992 Dec;29:888-91; Suhr OB et al. Transplantation, 2016 Feb;100:373-81; Ungerer MN et al. Amyloid, 2021 Jun;28:91-99). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
OMIM	RCV000014386	SCV000034635	pathogenic	Familial amyloid neuropathy	1992-12-01	no assertion criteria provided	literature only