Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000668656 | SCV000793290 | uncertain significance | Tay-Sachs disease | 2017-08-09 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001805791 | SCV002051189 | uncertain significance | not specified | 2021-12-17 | criteria provided, single submitter | clinical testing | Variant summary: HEXA c.736G>A (p.Ala246Thr) 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 251682 control chromosomes (gnomAD and publication data). c.736G>A has been reported in the literature in individuals affected with Tay-Sachs Disease (Montalvo_2005, Lee_2008, Gort_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Invitae | RCV000668656 | SCV002242465 | pathogenic | Tay-Sachs disease | 2023-08-29 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 246 of the HEXA protein (p.Ala246Thr). This variant is present in population databases (rs758166013, gnomAD 0.0009%). This missense change has been observed in individual(s) with hexosaminidase A deficiency (PMID: 16088929, 18648917, 22789865). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553250). 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. |
| Mendelics | RCV000668656 | SCV002517274 | likely pathogenic | Tay-Sachs disease | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000668656 | SCV002767338 | likely pathogenic | Tay-Sachs disease | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 20, catalytic domain (DECIPHER). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Ala246Ser) has been classified as a VUS by a diagnostic laboratory while p.(Ala246Arg) has been identified in a Tay-Sachs patient (PMID: 22789865). (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. Despite being found in at least two Tay-Sachs patients, it has been classified as a VUS by a diagnostic laboratory (ClinVar; PMID: 16088929, 18648917). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000520.5:c.1444G>A; p.(Glu482Lys)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |