ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.805G>C (p.Gly269Arg) (rs121907954)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000416443 SCV001416055 likely pathogenic Tay-Sachs disease 2020-08-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 269 of the HEXA protein (p.Gly269Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 7 of the HEXA coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another HEXA variant in an individual affected with Tay–Sachs disease (PMID: 27896118). ClinVar contains an entry for this variant (Variation ID: 375357). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the c.805 nucleotide in the HEXA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2522679, 20363167). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000416443 SCV000494217 pathogenic Tay-Sachs disease 2012-12-18 no assertion criteria provided research

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