GeneBe

NM_000521.4:c.1597C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000521.4(HEXB):​c.1597C>T​(p.Arg533Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

13
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.88
Variant links:
Genes affected
HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a helix (size 16) in uniprot entity HEXB_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000521.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 5-74720731-C-T is Pathogenic according to our data. Variant chr5-74720731-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 435415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-74720731-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEXBNM_000521.4 linkc.1597C>T p.Arg533Cys missense_variant Exon 13 of 14 ENST00000261416.12 NP_000512.2 P07686A0A024RAJ6
HEXBNM_001292004.2 linkc.922C>T p.Arg308Cys missense_variant Exon 13 of 14 NP_001278933.1 P07686Q5URX0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEXBENST00000261416.12 linkc.1597C>T p.Arg533Cys missense_variant Exon 13 of 14 1 NM_000521.4 ENSP00000261416.7 P07686

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251256
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135768
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461100
Hom.:
0
Cov.:
30
AF XY:
0.0000261
AC XY:
19
AN XY:
726926
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000731
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Sandhoff disease Pathogenic:10
Mar 16, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 19, 2016
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 12, 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 cysteine, which is neutral and slightly polar, at codon 533 of the HEXB protein (p.Arg533Cys). This variant is present in population databases (rs764552042, gnomAD 0.006%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 21567908, 22848519, 23010210, 27682710). ClinVar contains an entry for this variant (Variation ID: 435415). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXB protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HEXB function (PMID: 22848519). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 10, 2020
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 30, 2018
Counsyl
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 22, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense c.1597C>T (p.Arg533Cys) variant in the HEXB gene which is located in a mutational hot spot has been reported previously in a compound heterozygous and homozygous state in individuals affected with Sandhoff Disease. Experimental studies have shown that this missense change affects HEXB function (Dastsooz et al., 2018; Zampieri et al., 2012). Different amino acid change affecting codon 533 (p.Arg533His) is reported as a known pathogenic variant. The amino acid Arg at position 533 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg533Cys in HEXB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

May 28, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 26, 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: HEXB c.1597C>T (p.Arg533Cys) 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 allele was found at a frequency of 3.2e-05 in 246212 control chromosomes (gnomAD and publication). c.1597C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Sandhoff Disease with limited or absent Hex activity (Gort_2012, Aryan_2012, Kaya_2011, Zampieri_2012). These data indicate that the variant is very likely to be associated with disease. Two CllinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.46
T;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;.;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
0.98
D
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-7.3
D;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0050
D;D;D
Vest4
0.91
MutPred
0.83
.;Loss of MoRF binding (P = 0.0183);.;
MVP
1.0
MPC
0.84
ClinPred
1.0
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.95

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.

Other links and lift over

dbSNP: rs764552042; hg19: chr5-74016556; COSMIC: COSV54670393; COSMIC: COSV54670393; API