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

dbSNP: rs121907954

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416443	SCV001416055	likely pathogenic	Tay-Sachs disease	2021-11-26	criteria provided, single submitter	clinical testing	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. 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. Variants that disrupt 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. 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"). ClinVar contains an entry for this variant (Variation ID: 375357). This missense change has been observed in individual(s) with Tay–Sachs disease (PMID: 27896118). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 269 of the HEXA protein (p.Gly269Arg). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000416443	SCV004038794	likely pathogenic	Tay-Sachs disease	2023-08-22	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.805G>C (p.Gly269Arg) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251438 control chromosomes (gnomAD). c.805G>C has been reported in the literature in one individual affected with Tay-Sachs Disease and one individual affected with central nervous system white matter abnormalities (examples: Sheth _2014 and Kaur_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same codon (c.805G>A , p.Gly269Ser) is classified pathogenic internally and in ClinVar (CV ID 3898). This suggests that this residue may be clinically significant. The following publications have been ascertained in the context of this evaluation (PMID: 34302356, 27896118). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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