ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00001  dbSNP: rs786204721
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169541 SCV000221026 likely pathogenic Tay-Sachs disease 2015-01-15 criteria provided, single submitter literature only
GeneDx RCV000255876 SCV000321767 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing The c.2T>C pathogenic variant in the HEXA gene has been reported previously in the compound heterozygous state in two unrelated individuals with acute late infantile onset Tay-Sachs disease (Harmon et al., 1993; Montalvo et al., 2005). As this variant alters the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. The c.2T>C variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.2T>C as a pathogenic variant.
Invitae RCV000169541 SCV000629534 pathogenic Tay-Sachs disease 2021-09-21 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the HEXA mRNA. The next in-frame methionine is located at codon 193. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individual(s) with PMID: 16088929, 8445615, Invitae (Tay-Sachs disease). ClinVar contains an entry for this variant (Variation ID: 189126). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000169541 SCV000746513 pathogenic Tay-Sachs disease 2018-08-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV000169541 SCV000807238 pathogenic Tay-Sachs disease 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 6-year-old female with developmental regression, slurred speech, intellectual disability, spasticity, epilepsy, ataxia, dystonia, failure to thrive, structural brain abnormalities, nystagmus, scoliosis, constipation, swallowing difficulties. A cousin died at 15y with regression and ataxia.
Eurofins NTD LLC (GA) RCV000255876 SCV000854841 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000169541 SCV001367375 pathogenic Tay-Sachs disease 2018-10-10 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169541 SCV001821351 pathogenic Tay-Sachs disease 2021-08-23 criteria provided, single submitter clinical testing Variant summary: HEXA c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249908 control chromosomes. c.2T>C has been reported in the literature in individuals affected with Tay-Sachs Disease (e.g. Harmon_1993, Montalvo_2005). These data indicate that the variant is associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Harmon_1993). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. In addition, other variants affecting the start codon (c.1A>C, c.1A>T, c.1A>G) have been reported to associate with Tay-Sachs disease (HGMD database). Based on the evidence outlined above, the variant was classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000169541 SCV000494202 pathogenic Tay-Sachs disease 2015-07-18 no assertion criteria provided research
Natera, Inc. RCV000169541 SCV002089771 pathogenic Tay-Sachs disease 2017-03-17 no assertion criteria provided clinical testing

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