Submissions for variant NM_000520.6(HEXA):c.748G>A (p.Gly250Ser)

dbSNP: rs1057521137

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443171	SCV000521180	pathogenic	not provided	2019-09-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; Enzymatic activity in a cell model demonstrated a decrease to 4% of WT.; Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17259242, 7717398)
Counsyl	RCV000675102	SCV000800638	uncertain significance	Tay-Sachs disease	2017-12-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000443171	SCV002064497	likely pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the HEXA gene demonstrated a sequence change, c.748G>A, in exon 7 that results in an amino acid change, p.Gly250Ser. This sequence change is absent in the gnomAD population database. This sequence change does not appear to have been described in individuals with HEXA-related disorders. However, a different sequence change affecting the same amino acid residue (p.Gly250Asp) has been described in a family with juvenile onset Tay Sachs disease (PMID: 1301189). The p.Gly250Ser change affects a highly conserved amino acid residue located in a domain of the HEXA protein that is known to be functional. The p.Gly250Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Gly250Ser disrupts the activity of the HEXA protein (PMIDs: 7717398, 17259242). Collectively this evidence indicates p.Gly250Ser is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675102	SCV003242132	uncertain significance	Tay-Sachs disease	2022-07-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 250 of the HEXA protein (p.Gly250Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. ClinVar contains an entry for this variant (Variation ID: 381668). 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. Experimental studies have shown that this missense change affects HEXA function (PMID: 17259242). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987533	SCV004803494	uncertain significance	not specified	2024-01-17	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.748G>A (p.Gly250Ser) 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 was absent in 251484 control chromosomes. To our knowledge, c.748G>A has not been reported in the literature in individuals affected with Tay-Sachs Disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant results in 10%-15% of normal enzymatic activity in vitro (e.g. Martin_2007). The following publication has been ascertained in the context of this evaluation (PMID: 17259242). ClinVar contains an entry for this variant (Variation ID: 381668). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.