ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.805G>A (p.Gly269Ser) (rs121907954)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168285 SCV000218959 pathogenic Tay-Sachs disease 2018-05-10 criteria provided, single submitter clinical testing This sequence change falls at the last nucleotide of exon 7 of the HEXA mRNA and it replaces glycine with serine at codon 269 of the HEXA protein (p.Gly269Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs121907954, ExAC 0.02%). This variant has been reported in individuals affected with adult onset Tay-Sachs disease also known as adult GM2-gangliosidosis. In these individuals this variant was present as compound heterozygous with other infantile onset Tay-Sachs alleles (PMID: 2522679). This is a high frequency allele in the Ashkenazi Jewish population with an obligate carrier frequency of 4% (PMID: 2220809). ClinVar contains an entry for this variant (Variation ID: 3898). Experimental studies have shown that this sequence change results in a drastically reduced enzymatic activity (PMID: 2522679, 20363167). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000434025 SCV000232069 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000434025 SCV000513236 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing The G269S variant in the HEXA gene is a common pathogenic variant in the Ashkenazi Jewish population and has been reported previously in association with adult-onset Tay-Sachs disease (Kaback and Desnick, 2011). Functional analysis of G269S indicates that it forms a defective alpha-subunit which fails to associate with the beta-subunit thus resulting in significantly reduced beta-hexosaminidase activity (Paw et al., 1989; Navon et al., 1989; Ohno et al., 2008). The G269S variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G269S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Therefore we interpret G269S to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000168285 SCV000697175 pathogenic Tay-Sachs disease 2017-03-31 criteria provided, single submitter clinical testing Variant summary: The HEXA c.805G>A (p.Gly269Ser) variant involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Brown_1993, further supports these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 12/121408 (1/10121), which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant of 1/715. Multiple publications have cited the variant in affected homozygote and compound heterozygote individuals, predominantly in Late-Onset TSD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000168285 SCV000894058 pathogenic Tay-Sachs disease 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000168285 SCV001194013 pathogenic Tay-Sachs disease 2019-10-18 criteria provided, single submitter clinical testing NM_000520.4(HEXA):c.805G>A(G269S) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with the adult-onset form of disease. Sources cited for classification include the following: PMID 15714079, 22006919, 10852376, 8343225, 19815695, 8328462, 2278539, 2522660, and 2522679. Classification of NM_000520.4(HEXA):c.805G>A(G269S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000434025 SCV001249188 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
OMIM RCV000004104 SCV000024270 pathogenic Gm2-gangliosidosis, adult 2008-08-01 no assertion criteria provided literature only
Myriad Women's Health, Inc. RCV000168285 SCV000485124 pathogenic Tay-Sachs disease 2016-02-05 no assertion criteria provided clinical testing

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