NM_000520.6:c.805G>A

Variant names:

• chr15-72350518-C-T
• rs121907954
• NM_000520.6:c.805G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000520.6(HEXA):​c.805G>A​(p.Gly269Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G269R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: HEXA NM_000520.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 7.81
• Publications: 72 publications found

Genes affected

HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

HEXA Gene-Disease associations (from GenCC):

• Tay-Sachs disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000261460 (HGNC:58304):

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000520.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-72350518-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 15-72350518-C-T is Pathogenic according to our data. Variant chr15-72350518-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000520.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	NM_000520.6	MANE Select	c.805G>A	p.Gly269Ser	missense splice_region	Exon 7 of 14	NP_000511.2
	HEXA	NM_001318825.2		c.838G>A	p.Gly280Ser	missense splice_region	Exon 7 of 14	NP_001305754.1
	HEXA	NR_134869.3		n.847G>A		splice_region non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.805G>A	p.Gly269Ser	missense splice_region	Exon 7 of 14	ENSP00000268097.6
	HEXA	ENST00000567159.5	TSL:1	c.805G>A	p.Gly269Ser	missense splice_region	Exon 7 of 13	ENSP00000456489.1
	ENSG00000261460	ENST00000570175.1	TSL:1	n.1872C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251438 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.000146 AC: 162 AN: 1111966

Other (OTH) AF: 0.000166 AC: 10 AN: 60380

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000292 Hom.: 1

Bravo AF: 0.000140

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:15

Mar 06, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.014%).Predicted Consequence/Location:Missense variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 2522679). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (> 0.75, sensitivity 0.96 and precision 0.92)].The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003898 / PMID: 2522679). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 2522679). Different missense changes at the same codon (p.Gly269Arg, p.Gly269Asp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000375357, VCV000842051 / PMID: 9150157).Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 10, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 16, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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]

Oct 18, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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

Mar 31, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Mar 29, 2023

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 16, 2019

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

Jul 19, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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

Aug 29, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.

Aug 05, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

not provided Pathogenic:5

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HEXA: PM3:Very Strong, PM1, PM5, PM2:Supporting, PP3, PS3:Supporting

May 09, 2022

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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.

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 26, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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)

HEXA-related disorder Pathogenic:1

Mar 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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.

Inborn genetic diseases Pathogenic:1

Apr 14, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Gm2-gangliosidosis, adult Pathogenic:1

Aug 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	0.70	N
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.93
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.98	D
Vest4		0.74
MVP		0.99
MPC		0.75
ClinPred		0.51	D
GERP RS		5.9
Varity_R		0.82
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121907954; hg19: chr15-72642859;