ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1385A>T (p.Glu462Val) (rs863225434)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
FRIGE's Institute of Human Genetics RCV000202369 SCV000257367 pathogenic Tay-Sachs disease 2011-10-01 criteria provided, single submitter clinical testing The mutation p.E462V was found in ten unrelated families from India indicating a founder effect.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000202369 SCV000898736 pathogenic Tay-Sachs disease 2018-09-13 criteria provided, single submitter clinical testing HEXA NM_000520.5 exon 12 p.Glu462Val (c.1385A>T): This variant has been reported in the literature in a homozygous or compound heterozygous state with another pathogenic variant, in at least 8 individuals of Indian (Gujarat) ancestry with infantile Tay-Sachs Disease (TSD), suggesting a founder effect (Mistri 2012 PMID:22723944, Sheth 2014 PMID:27896118, Sheth 2018 PMID:29973161). This variant is present in 0.003% (1/30762) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-72638612-T-A) with no homozygotes identified. Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar (Variation ID:218134). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. Computational structural analyses revealed that this residue is located within the active site of the alpha subunit of hexosamindase A and support that this variant may impact the protein (Mistri 2012 PMID:22723944). In summary, this variant is classified as pathogenic.

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