15-72345476-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000520.6(HEXA):c.1496G>A(p.Arg499His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.56

Variant links:

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 links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

PP5

Variant 15-72345476-C-T is Pathogenic according to our data. Variant chr15-72345476-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72345476-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.1496G>A	p.Arg499His	missense_variant	Exon 13 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1529G>A	p.Arg510His	missense_variant	Exon 13 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1281G>A		non_coding_transcript_exon_variant	Exon 11 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1496G>A	p.Arg499His	missense_variant	Exon 13 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.578G>A		non_coding_transcript_exon_variant	Exon 5 of 16	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251458

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000718

AC:

105

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:12

Feb 12, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HEXA c.1496G>A (p.Arg499His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant, c.1496G>A, was observed with an allele frequency of 5.7e-05 in 246362 control chromosomes (gnomAD and publication controls). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.7e-05 vs 0.0014), allowing no conclusion about variant significance. The variant, c.1496G>A, has been reported in the literature in multiple compound heterozygote individuals affected with Tay-Sachs Disease, while some present with a subacute phenotype or late-onset (adult and juvenile). Multiple clinical diagnostic laboratories via ClinVar submissions (evaluations performed after 2014) classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 02, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in the compound heterozygote state in individuals affected with infantile Tay-Sachs disease and in individuals with the juvenile onset form (PMID 29214523, 31367523, 18490185, 2144098). ClinVar contains an entry for this variant (Variation ID: 3899). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (14/251458) and thus is presumed to be rare. The c.1496G>A (p.Arg499His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1496G>A (p.Arg499His) variant is classified as Likely Pathogenic. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 13 of the HEXA gene that results in the amino acid substitution of Histidine for Arginine at codon 499 was detected. The observed variant c.1496G>A (p.Arg499His) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Dec 14, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

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 v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003899). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14577003 , 29214523). A different missense change at the same codon (p.Arg499Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003915). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 17, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.1496G>A (p.Arg499His) in HEXA gene has been reported previously in homozygous andcompound heterozygous state in individuals affected with HEXA related disorder (Stepien KM et al. 2018; Matsuzawa F et al. 2003).Functional studies demonstrate a damaging effect (retention of the Hex alpha-subunit in the ER and posterior degradation alongwith a lower value of the solvent-accessible surface area) (Paw et al., 1990). The p.Arg499His variant has allele frequency of 0.01%in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). Multiple lines ofcomputational evidence (Polyphen -Probably damaging, SIFT - Damaging and Mutation Taster - Disease causing) predict adamaging effect on protein structure and function for this variant. The amino acid change p.Arg499His in HEXA is predicted asconserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 499 is changed to a His changing proteinsequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classifiedas Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the HEXA protein (p.Arg499His). This variant is present in population databases (rs121907956, gnomAD 0.03%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 2144098, 14577003, 17237499). ClinVar contains an entry for this variant (Variation ID: 3899). 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) indicates that this missense variant is expected to disrupt HEXA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

May 02, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Feb 21, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (retention of the Hex alpha-subunit in the ER and posterior degradation along with a lower value of the solvent-accessible surface area) (PMID: 2140574); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26984043, 1833974, 2140574, 18490185, 34288098, 19091716, 35936646, 34302356, 31367523, 24767253, 22441121, 17237499, 33240792, 29214523) -

Nov 06, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HEXA: PP4:Strong, PM2, PM3, PM5 -

Gm2-gangliosidosis, juvenile

Pathogenic:1

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases

Pathogenic:1

Dec 27, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1496G>A (p.R499H) alteration is located in coding exon 13 of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1496, causing the arginine (R) at amino acid position 499 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (14/251458) total alleles studied. The highest observed frequency was 0.03% (10/30614) of South Asian alleles. This alteration has been reported in multiple individuals with Tay-Sachs disease with a second HEXA alteration (Paw, 1990; Maegawa, 2006; Stepien, 2018; Ou, 2019). This amino acid position is highly conserved in available vertebrate species. The p.R499H amino acid is located in the GH20_HexA_HexB-like domain. Biosynthetic studies of the R499H alteration revealed the synthesis of an abnormal a-subunit which did not associate with the b-subunit. It was not processed into the mature lysosomal form and appeared to be retained and degraded in the endoplasmic reticulum, possibly due to misfolding. However some residual enzyme activity (~3%) was observed (Paw, 1990). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.98

MVP

0.99

MPC

0.84

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over