ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1435G>A (p.Ala479Thr)

gnomAD frequency: 0.00038  dbSNP: rs145012038
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000384004 SCV000340739 benign not specified 2016-04-15 criteria provided, single submitter clinical testing
Counsyl RCV000505691 SCV000599896 likely benign Tay-Sachs disease 2017-08-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000384004 SCV000919504 benign not specified 2022-06-29 criteria provided, single submitter clinical testing Variant summary: HEXA c.1435G>A (p.Ala479Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain 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 0.00082 in 277154 control chromosomes, predominantly at a frequency of 0.0084 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in HEXA causing Tay-Sachs Disease phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1435G>A has been reported in the literature, without strong evidence for causality (Strom_2013). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified variant as VUS (n=1), likely benign (n=3), and benign (n=4). One of these labs also published an abstract in which they tested 4-5 patient samples for the variant of interest and found HexA enzyme analysis to show negative Tay-Sachs carrier state for all subjects (Counsyl abstract from Molecular Genetics and Metabolism, 2018). Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000862163 SCV001002628 benign not provided 2019-03-04 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000862163 SCV001149514 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000505691 SCV001653477 likely benign Tay-Sachs disease 2021-05-18 criteria provided, single submitter clinical testing
Invitae RCV000505691 SCV001725342 benign Tay-Sachs disease 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000862163 SCV001850209 benign not provided 2021-04-12 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 31293106)
Natera, Inc. RCV000505691 SCV002085662 likely benign Tay-Sachs disease 2018-03-22 no assertion criteria provided clinical testing

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