Submissions for variant NM_000520.6(HEXA):c.590A>C (p.Lys197Thr)

dbSNP: rs121907973

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674617	SCV000799985	uncertain significance	Tay-Sachs disease	2018-05-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508770	SCV001715122	likely pathogenic	not provided	2019-04-23	criteria provided, single submitter	clinical testing	PS3, PM2, PM3, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797585	SCV002041571	uncertain significance	not specified	2021-11-28	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.590A>C (p.Lys197Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.590A>C has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with adult onset Tay-Sachs Disease who has been subsequently cited by others (example, Akli_1993). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674617	SCV002229566	uncertain significance	Tay-Sachs disease	2021-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with threonine at codon 197 of the HEXA protein (p.Lys197Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs121907973, ExAC 0.001%). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 8490625). ClinVar contains an entry for this variant (Variation ID: 3927). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Studies have shown that this variant does not significantly alter or has an unclear effect on HEXA gene expression (PMID: 8490625). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001508770	SCV002497799	likely pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	HEXA: PM3:Strong, PM2, PP3, PP4
OMIM	RCV000004133	SCV000024299	pathogenic	Gm2-gangliosidosis, late onset	1993-01-01	no assertion criteria provided	literature only