ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.2T>C (p.Met1Thr) (rs786204721)

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Total submissions: 8
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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 2017-05-12 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the HEXA mRNA. While it is expected to result in an absent or disrupted protein product, alternate methionines downstream of the initiator codon could potentially rescue the translation initiation. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with other HEXA variants in individuals affected with Tay-Sachs disease (PMID: 16088929, 8445615, Invitae). In addition, different changes disrupting the initiator codon (c.1A>G and c.1A>T) have also been reported in individuals affected with Tay-Sach disease or GM2-gangliosidosis (PMID: 21796138, 15108204). ClinVar contains an entry for this variant (Variation ID: 189126). Experimental studies have shown that this variant is associated with diminished HEXA enzyme activity in patient cells (PMID: 16088929, 8445615). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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.
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

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