15-72353105-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000520.6(HEXA):c.533G>A(p.Arg178His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. 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. R178C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 7.81

Publications

40 publications found

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 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

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000520.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-72353106-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 15-72353105-C-T is Pathogenic according to our data. Variant chr15-72353105-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.533G>A	p.Arg178His	missense_variant	Exon 5 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.566G>A	p.Arg189His	missense_variant	Exon 5 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.575G>A		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.533G>A	p.Arg178His	missense_variant	Exon 5 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.412+2454G>A		intron_variant	Intron 3 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000478

AC:

AN:

251014

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461090

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726890

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33456

American (AMR)

AF:

0.000134

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000765

AC:

AN:

1111342

Other (OTH)

AF:

0.0000663

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41516

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68000

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000756

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:13

Aug 07, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM3 strong, PP1 strong, PP3 supporting, PP4 -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.R178H in HEXA (NM_000520.6) causes the same amino acid change as a previously established pathogenic variant. The R178H variant in the HEXA gene has previously been reported in association with the B1 variant phenotype of TaySachs disease, and is a common pathogenic variant in the Portuguese population (dos Santos et al., 1991). The p.R178H variant is observed in 4/34,556 (0.0116%) alleles from individuals of Latino background in gnomAD Exomes and in 1/1,006 (0.0994%) alleles from individuals of European background in 1000 Genomes. The p.R178H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 178 of HEXA is conserved in all mammalian species. The nucleotide c.533 in HEXA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Structural analysis of the alpha-subunit of beta-hexosaminidase indicated that the Arginine residue at position 178 is critical for substrate binding. For these reasons, this variant has been classified as Pathogenic. -

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.533G>A;p.(Arg178His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3896; PMID: 18490185; 17015493; 16088929; 8730294; 7551830; 1318511; 22789865) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 1831451) - PS3_supporting. The variant is present at low allele frequencies population databases (rs28941770– gnomAD 0.00001973%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg178His) was detected in trans with a pathogenic variant (PMID: 17015493; 16088929; 8730294; 7551830; 22789865) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 3912; 3897) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 8730294) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 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.533G>A (p.Arg178His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/120572 control chromosomes at a frequency of 0.0000664, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant has been reported in many TSD patients both as homozygotes and compound heterozygotes. This variant was shown to be associated with milder phenotype and later onset of disease. Structural studies showed codon R178 to be critical for substrate binding and the reaction intermediates, and R178H is predicted to affect the active site pocket. The effect is lager in R178L and R178C than in R178H, which could explain the difference in clinical phenotype (Ohno_2008). The fact that variants R178L, R178L, and R178H have been reported to be associated with TSD suggest the functional important of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Nov 27, 2023

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: 0.005%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.99 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.91 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003896 /PMID: 2961848 /3billion dataset). Different missense changes at the same codon (p.Arg178Cys, p.Arg178Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003897, VCV000003912 /PMID: 1833974, 2137287). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 08, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 previously reported in patients with Hexosaminidase A deficiency (PMID: 22789865, 1832817). Missense variation is an established mechanism of disease for HEXA-related disorders (HGMD). The c.533G>A (p.Arg178His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (12/251014) and thus is presumed to be rare. The c.533G>A (p.Arg178His) 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.533G>A (p.Arg178His) variant is classified as Pathogenic. -

Dec 02, 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 178 of the HEXA protein (p.Arg178His). This variant is present in population databases (rs28941770, gnomAD 0.01%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). It is commonly reported in individuals of Spanish, Portugese, Italian ancestry (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). ClinVar contains an entry for this variant (Variation ID: 3896). 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 80%. Experimental studies have shown that this missense change affects HEXA function (PMID: 1831451). For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000520.4(HEXA):c.533G>A(R178H) is classified as pathogenic in the context of hexosaminidase A deficiency, and is associated with the juvenile / chronic form of the disease. Sources cited for classification include the following: PMID 22441121, 17015493, 2961848, 8730294, 20100466, 22789865, 7551830, 16088929, 1832817 and 2973311. Classification of NM_000520.4(HEXA):c.533G>A(R178H) 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. -

Jan 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Nov 16, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Common pathogenic variant identified in Spanish, Portuguese, and Italian populations and is associated with late-onset Tay Sachs disease (PMID: 22789865); Not observed at significant frequency in large population cohorts (gnomAD); 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: 22975760, 2521932, 1318511, 21228398, 26286102, 34712575, 10584247, 2973311, 28923328, 16088929, 2961848, 27362553, 1832817, 34440436, 32005694, 31589614, 33240792, 33258288, 18490185, 22789865, 2137287) -

Jul 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 04, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HEXA-related disorder

Pathogenic:1

Jun 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HEXA c.533G>A variant is predicted to result in the amino acid substitution p.Arg178His. This variant, also referred as the DN-allele, has been repeatedly reported in individuals with Tay-Sachs disease in both the homozygous and compound heterozygous state (Ohno et al. 1988. PubMed ID: 2961848; King et al. 2020. PubMed ID: 33240792; Gort et al. 2012. PubMed ID: 22789865; Montalvo et al. 2005. PubMed ID: 16088929; Maegawa et al. 2006. PubMed ID: 17015493; Giraud et al. 2010. PubMed ID: 20100466). HEXA enzymatic activity in patient's serum and fibroblasts is shown to be significantly reduced (Table 1, Gort et al. 2012. PubMed ID: 22789865). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD and has been reported as pathogenic by multiple laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3896/). Additionally, different missense changes impacting the same amino acid (p.Arg178Cys and Arg178Leu) have been reported in individuals with Tay-Sachs disease, suggesting that the Arg178 residue is critical to protein function (Tanaka et al. 1990. PubMed ID: 2137287; Triggs-Raine et al. 1991. PubMed ID: 1833974). Taken together, the Arg178His variant is interpreted as pathogenic. -

Global developmental delay

Pathogenic:1

Nov 01, 2019

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

homozygous -

Inborn genetic diseases

Pathogenic:1

Nov 06, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R178H pathogenic mutation (also known as c.533G>A), located in coding exon 5 of the HEXA gene, results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties. This pathogenic mutation was first described in trans with a frameshift mutation in a patient diagnosed with Tay-Sachs disease and demonstrating decreased enzymatic activity. In five additional cases from this study, they detected one homozygous and four heterozygous patients, primarily diagnosed in early childhood with a slower progression of disease (Tanaka A, Am. J. Hum. Genet. 1990 Feb; 46(2):329-39). In further studies, individuals homozygous for this mutation present with the juvenile form of Tay-Sachs disease. There is a more variable presentation when this mutation occurs with another pathogenic allele (dos Santos MR, Am. J. Hum. Genet. 1991 Oct; 49(4):886-90 and Gort L, Gene 2012 Sep; 506(1):25-30). This pathogenic mutation results in the B1 variant form of Tay-Sachs disease, which demonstrates normal activity if exposed to artificial substrates but is defective with natural ligand (Gort L, Gene 2012 Sep; 506(1):25-30). Based on the supporting evidence, p.R178H is interpreted as a disease-causing mutation. -

Tay-Sachs disease, B1 variant

Pathogenic:1

Apr 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hexa, dn allele

Pathogenic:1

Apr 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.5

H;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.99

MVP

1.0

MPC

0.84

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.97

Mutation Taster

=197/103

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over