NM_000521.4(HEXB):c.761T>C (p.Leu254Ser) AND Sandhoff disease

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 4, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000993713.4

Allele description [Variation Report for NM_000521.4(HEXB):c.761T>C (p.Leu254Ser)]

NM_000521.4(HEXB):c.761T>C (p.Leu254Ser)

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.761T>C (p.Leu254Ser)

HGVS:

NC_000005.10:g.74705310T>C
NG_009770.2:g.70288T>C
NM_000521.4:c.761T>CMANE SELECT
NM_001292004.2:c.86T>C
NP_000512.2:p.Leu254Ser
NP_001278933.1:p.Leu29Ser
NC_000005.9:g.74001135T>C
NC_000005.9:g.74001135T>C

Protein change:

L254S

Links:

dbSNP: rs771103635

NCBI 1000 Genomes Browser:

rs771103635

Molecular consequence:

NM_000521.4:c.761T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001292004.2:c.86T>C - 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

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recombinase A, partial [Streptococcus thermophilus]
recombinase A, partial [Streptococcus thermophilus]
gi|661512593|gb|AIE15475.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000999190	Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University	no assertion criteria provided	Likely pathogenic (Nov 26, 2019)	germline	research
SCV002246439	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 4, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33407268, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000999190

Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University

no assertion criteria provided

Likely pathogenic
(Nov 26, 2019)

germline

research

SCV002246439

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 4, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
South East Asian	germline	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients.

Tim-Aroon T, Wichajarn K, Katanyuwong K, Tanpaiboon P, Vatanavicharn N, Sakpichaisakul K, Kongkrapan A, Eu-Ahsunthornwattana J, Thongpradit S, Moolsuwan K, Satproedprai N, Mahasirimongkol S, Lerksuthirat T, Suktitipat B, Jinawath N, Wattanasirichaigoon D.

BMC Pediatr. 2021 Jan 7;21(1):22. doi: 10.1186/s12887-020-02481-3.

PubMed [citation]

PMID:: 33407268
PMCID:: PMC7789739

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

Details of each submission

From Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, SCV000999190.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South East Asian	1	not provided	not provided	research	not provided

Description

c.761C>T (p.Leu254Ser) likely pathogenic and that it was observed in an individual with another pathogenic/likely pathogenic variant in the same gene on the other chromosome, it was c.1652G>A (p.Cys551Tyr). p.Cys551Tyr is the most common mutation among Thai patients with infantile Sandhoff disease.

Description

The patient showed classical presentation of with infantile onset Sandhoff disease plus deficient enzyme activity in leukocytes.

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

From Invitae, SCV002246439.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 800653). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 33407268). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 254 of the HEXB protein (p.Leu254Ser).

#	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

Last Updated: May 7, 2024

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