Submissions for variant NM_000520.6(HEXA):c.1490A>G (p.Tyr497Cys)

gnomAD frequency: 0.00007  dbSNP: rs147502219

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513686	SCV000609734	uncertain significance	not provided	2017-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855657	SCV000697164	uncertain significance	not specified	2019-05-03	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.1490A>G (p.Tyr497Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251466 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (4.4e-05 vs 0.0014), allowing no conclusion about variant significance. c.1490A>G has not, to our knowledge, been reported in the literature in affected individuals, although a clinical diagnostic laboratory has listed the variant as 'pathogenic', without any additional information to allow for an independent evaluation (Chin 2009). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000669111	SCV000793824	uncertain significance	Tay-Sachs disease	2017-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000513686	SCV002520152	uncertain significance	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Reported in association with Tay-Sachs disease in the published literature, although clinical information, zygosity, and familial segregation information were not included (Chin et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31367523, 19644708)
Invitae	RCV000669111	SCV003273447	uncertain significance	Tay-Sachs disease	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 497 of the HEXA protein (p.Tyr497Cys). This variant is present in population databases (rs147502219, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of HEXA-related conditions (PMID: 19644708). ClinVar contains an entry for this variant (Variation ID: 445397). 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. 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	RCV000513686	SCV004132777	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	HEXA: PM2
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000513686	SCV001741176	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513686	SCV001964933	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000669111	SCV002085657	uncertain significance	Tay-Sachs disease	2018-09-16	no assertion criteria provided	clinical testing