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

gnomAD frequency: 0.00015  dbSNP: rs121907954

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168285	SCV000218959	pathogenic	Tay-Sachs disease	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 269 of the HEXA protein (p.Gly269Ser). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121907954, gnomAD 0.07%). This missense change has been observed in individuals with Tay-Sachs disease, also known as adult GM2-gangliosidosis (PMID: 2522679). ClinVar contains an entry for this variant (Variation ID: 3898). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HEXA function (PMID: 2522679, 20363167). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000434025	SCV000232069	pathogenic	not provided	2017-08-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000434025	SCV000513236	pathogenic	not provided	2019-11-26	criteria provided, single submitter	clinical testing	Common pathogenic variant in the Ashkenazi Jewish population and associated with adult-onset Tay-Sachs disease (Kaback et al., 2011); Functional analysis of G269S indicate 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); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27033294, 21228398, 27351546, 2522679, 18490185, 22975760, 2522660, 31076878, 22006919, 27682588, 2278539)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Genetics, 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.‚Äã
CeGaT Center for Human Genetics Tuebingen	RCV000434025	SCV001249188	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	HEXA: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000168285	SCV001369403	likely pathogenic	Tay-Sachs disease	2019-08-29	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000434025	SCV001448072	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000168285	SCV001530446	pathogenic	Tay-Sachs disease	2018-05-16	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 2522679, 21228398, 27682588, 22975760, 18490185, 22006919]
Revvity Omics, Revvity	RCV000168285	SCV002024983	pathogenic	Tay-Sachs disease	2021-06-12	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000168285	SCV002579018	pathogenic	Tay-Sachs disease	2022-07-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408450	SCV002675688	pathogenic	Inborn genetic diseases	2017-04-14	criteria provided, single submitter	clinical testing	The c.805G>A pathogenic mutation (also known as p.G269S), located in coding exon 7 of the HEXA gene, results from a G to A substitution at nucleotide position 805. This change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glycine at codon 269 to serine, an amino acid with similar properties. This mutation was first reported in eight adults with Tay-Sachs disease from five unrelated families who were compound heterozygous for this alteration and an infantile-onset mutation (Navon R et al. Science, 1989 Mar;243:1471-4). In another study, this mutation was detected in three homozygous adults with Tay-Sachs disease; family studies confirmed biparental inheritance in one of these individuals (Navon R et al. Am. J. Hum. Genet., 1990 Apr;46:817-21). Although this mutation was predicted to have small impact on the protein structure, extracts from cells expressing G269S showed markedly reduced hexosaminidase activity (Navon R et al. Science, 1989 Mar;243:1471-4; Ohno K et al. Mol. Genet. Metab., 2008 Aug;94:462-8). Based on the available evidence, c.805G>A is classified as a pathogenic mutation.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000168285	SCV002764731	pathogenic	Tay-Sachs disease	2022-08-05	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000168285	SCV002767808	pathogenic	Tay-Sachs disease	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 42 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Although this variant is located within the splice region and the nucleotide is highly conserved, in silico programs do not predict abberant splicing. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 20, catalytic domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in ClinVar and in many individuals with the adult form of Tay-Sachs disease (PMIDs: 31076878, 27033294). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000168285	SCV004032468	pathogenic	Tay-Sachs disease	2023-03-29	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV000168285	SCV004037345	pathogenic	Tay-Sachs disease	2019-10-16	criteria provided, single submitter	clinical testing	The c.805G>A (p.Gly269Ser) variant in HEXA substitutes a conserved glycine residue to a serine at amino acid position 269. This variant localizes to coding exon 7 of the HEXA gene (14 coding exons in total; NM_000520.6). Functional studies showed decreased enzyme levels due to destabilization of the a-subunit at physiological temperatures affecting the alpha-beta dimerization (PMID: 8328462, 2522660, 2522679, 27682588). Protein modeling have shown that the mutation does not affect the active site which allows for some functionality, allowing for the later onset phenotype (PMID: 18490185). This variant is present in the Genome Aggregation Database (gnomAD) at an allele frequency of 42/282842 (no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple late-onset patients as homozygous or compound heterozygous with another pathogenic variant (PMID: 2278539, 31076878 & 2522679), and is reported in ClinVar as pathogenic (Variation ID: 3898). Missense variants causing different amino acid substitution at the same position have also been reported as pathogenic (PMID: 27896118).
PreventionGenetics, part of Exact Sciences	RCV003924800	SCV004739342	pathogenic	HEXA-related condition	2024-02-01	criteria provided, single submitter	clinical testing	The HEXA c.805G>A variant is predicted to result in the amino acid substitution p.Gly269Ser. This variant has been documented to be causative for infantile and adult onset Tay-Sachs disease (Navon et al. 1989. PubMed ID: 2522679; Ohno et al. 2008. PubMed ID: 18490185; Deik and Saunders-Pullman. 2014. PubMed ID: 24327357; Steiner et al. 2016. PubMed ID: 27033294). Taken together, we interpret this variant as pathogenic.
OMIM	RCV000004104	SCV000024270	pathogenic	Gm2-gangliosidosis, adult	2008-08-01	no assertion criteria provided	literature only
OMIM	RCV001810397	SCV000024310	pathogenic	Gm2-gangliosidosis, late onset	1992-12-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000168285	SCV002086284	pathogenic	Tay-Sachs disease	2017-03-17	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000434025	SCV003839577	pathogenic	not provided	2022-05-09	no assertion criteria provided	clinical testing	DNA sequence analysis of the HEXA gene demonstrated a sequence change, c.805G>A, in exon 7 that results in an amino acid change, p.Gly269Ser. The p.Gly269Ser change affects a highly conserved amino acid residue located in a domain of the HEXA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly269Ser substitution. This pathogenic sequence change has previously been described in individuals with HEXA-related disorders and is the most common variant associated with late-onset Tay-Sachs disease (PMID: 27682588, 8328462, 15714079). This sequence change has been described in the gnomAD database with a frequency of 0.068% in the Ashkenazi Jewish subpopulation (dbSNP rs121907954). These collective evidences indicate that this sequence change is pathogenic. Bi-allelic pathogenic variants in the HEXA gene are associated with GM2-gangliosidosis or Tay-Sachs disease (OMIM# 272800), which is a progressive neurodegenerative disorder.