Submissions for variant NM_000520.6(HEXA):c.1393G>A (p.Asp465Asn)

gnomAD frequency: 0.00001  dbSNP: rs750727201

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670916	SCV000795832	uncertain significance	Tay-Sachs disease	2017-11-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001592851	SCV001822939	likely pathogenic	not provided	2018-12-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11317368, 24498621, 24583203)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670916	SCV002276976	likely pathogenic	Tay-Sachs disease	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 465 of the HEXA protein (p.Asp465Asn). This variant is present in population databases (rs750727201, gnomAD 0.003%). This missense change has been observed in individual(s) with Tay Sachs disease (PMID: 11317368; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555154). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HEXA protein function. 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.
Ambry Genetics	RCV002531267	SCV003613212	likely pathogenic	Inborn genetic diseases	2022-02-17	criteria provided, single submitter	clinical testing	The c.1393G>A (p.D465N) alteration is located in exon 12 (coding exon 12) of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1393, causing the aspartic acid (D) at amino acid position 465 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/251186) total alleles studied. The highest observed frequency was 0.003% (1/34554) of Latino alleles. This alteration has been reported homozygous in a patient with Tay Sachs disease. The 5 year old boy had exaggerated startle response, myoclonic jerks, progressive weakness, diminished muscle tone, and decreased eye contact. He eventually had loss of previously acquired skills, tonic seizures, hyperreflexia, increasing muscle stiffness and progressive spasticity, as well as a cherry red spot in the macula. There was no hepatomegaly or splenomegaly. His parents were enzymatically confirmed as Tay Sachs carriers and were found to be heterozygous for the c.1393G>A alteration (Alvarez-Rodríguez, 2001). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670916	SCV003934607	likely pathogenic	Tay-Sachs disease	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.1393G>A (p.Asp465Asn) results in a conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251186 control chromosomes (gnomAD). c.1393G>A has been reported in the literature in a homozygous individual affected with Tay-Sachs Disease (TSD) whose parents and extended family were enzymatically defined as TSD carriers (example: Alvarez-Rodriguez_2001). This individual also had two affected brothers however, authors did not specify if the affected siblings DNA analysis was performed. 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. The following publications have been ascertained in the context of this evaluation (PMID: 11317368, 24583203). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV000670916	SCV002085666	likely pathogenic	Tay-Sachs disease	2017-12-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907933	SCV004724646	likely pathogenic	HEXA-related disorder	2023-11-21	no assertion criteria provided	clinical testing	The HEXA c.1393G>A variant is predicted to result in the amino acid substitution p.Asp465Asn. This variant was reported in homozygous state in an individual with Tay-Sachs disease (TSD) and parents together with four other family members, who were heterozygotes for this variant, were enzymatically defined as TSD carriers (Alvarez-Rodriguez et al. 2001. PubMed ID: 11317368). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.