NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln) AND Sandhoff disease

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000669552.15

Allele description [Variation Report for NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln)]

NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln)

Gene:

HEXB:hexosaminidase subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q13.3

Genomic location:

Preferred name:

NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln)

HGVS:

NC_000005.10:g.74720648G>A
NG_009770.2:g.85626G>A
NG_011531.1:g.51570C>T
NM_000521.4:c.1514G>AMANE SELECT
NM_001292004.2:c.839G>A
NP_000512.2:p.Arg505Gln
NP_001278933.1:p.Arg280Gln
NC_000005.9:g.74016473G>A
NM_000521.3:c.1514G>A

Protein change:

R280Q; ARG505GLN

Links:

OMIM: 606873.0009; dbSNP: rs121907983

NCBI 1000 Genomes Browser:

rs121907983

Molecular consequence:

NM_000521.4:c.1514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001292004.2:c.839G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Sandhoff disease
Synonyms:: GM2-GANGLIOSIDOSIS, TYPE II; HEXOSAMINIDASES A AND B DEFICIENCY; Beta-hexosaminidase-beta-subunit deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010006; MedGen: C0036161; Orphanet: 796; OMIM: 268800

Recent activity

Clear Turn Off Turn On

cytochrome b, partial (mitochondrion) [Hipposideros cf. ruber]
cytochrome b, partial (mitochondrion) [Hipposideros cf. ruber]
gi|2096846136|gb|UBA14732.1|

Protein
recombination activator protein 2, partial [Hipposideros cf. ruber]
recombination activator protein 2, partial [Hipposideros cf. ruber]
gi|763551856|gb|AJQ24348.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000794314	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Sep 22, 2017)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12166653, 20926324, 23010210, 8950198, 20798201, 23759947, 22789865, 9562328, 8357844 Citation Link,
SCV001391079	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8950198, 12027830, 23759947, 8357844, 28492532
SCV001442639	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 18, 2020)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 22789865, 23010210, 20798201, 20926324, 9562328, 8950198, 12166653, 12027830, 23759947 Citation Link,
SCV002024988	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002084952	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 8, 2020)	germline	clinical testing
SCV005051826	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of an adult form of Sandhoff disease: substitution of glutamine for arginine at position 505 of the beta-chain of beta-hexosaminidase results in a labile enzyme.

Bolhuis PA, Ponne NJ, Bikker H, Baas F, Vianney de Jong JM.

Biochim Biophys Acta. 1993 Sep 8;1182(2):142-6.

PubMed [citation]

PMID:: 8357844

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000794314.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001391079.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 505 of the HEXB protein (p.Arg505Gln). This variant is present in population databases (rs121907983, gnomAD 0.01%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 8950198, 12027830, 23759947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3879). 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. Experimental studies have shown that this missense change affects HEXB function (PMID: 8357844). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442639.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: HEXB c.1514G>A (p.Arg505Gln) results in a conservative amino acid change located in the Glycoside hydroxylase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Four 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 251186 control chromosomes. c.1514G>A has been reported in the literature in multiple individuals affected with adult and juvenile onset Sandhoff Disease (example, Redonnet-Vernhet_1996, Hara_1998, Sakuraba_2002, Utsumi_2002, Delnooz_2010, Clarke_2011, Gort_2012, Sobek_2012, Yasui_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe impairment of normal enzyme activity (example, Redonnet-Vernhet_1996). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024988.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002084952.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051826.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine