Submissions for variant NM_000520.6(HEXA):c.902T>G (p.Met301Arg)

dbSNP: rs121907977

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000004139	SCV000957506	pathogenic	Tay-Sachs disease	2023-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 301 of the HEXA protein (p.Met301Arg). This variant is present in population databases (rs121907977, gnomAD 0.01%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 8490625, 33083013). ClinVar contains an entry for this variant (Variation ID: 3933). 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 HEXA protein function. For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV001250228	SCV001424436	pathogenic	Tay-Sachs disease, variant AB; Tay-Sachs disease		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000004139	SCV002578945	uncertain significance	Tay-Sachs disease	2022-03-30	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000004139	SCV003843895	likely pathogenic	Tay-Sachs disease	2020-02-21	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 8 of the HEXA gene that results in the amino acid substitution of Arginine for Methionine at codon 301 was detected. The observed variant c.902T>G (p.Met301Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004139	SCV003934608	likely pathogenic	Tay-Sachs disease	2023-05-03	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.902T>G (p.Met301Arg) 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 1.6e-05 in 251438 control chromosomes. c.902T>G has been reported in the literature in homozygous and compound heterozygous individuals affected with Tay-Sachs Disease (Akil_1993, Cheema_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8490625, 33083013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Pathogenic (n=1), Likely Pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000004139	SCV000024305	affects	Tay-Sachs disease	1993-01-01	no assertion criteria provided	literature only