NM_000521.4(HEXB):c.1242G>A (p.Lys414=) AND Sandhoff disease

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 5, 2023
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:: RCV000674299.4

Allele description [Variation Report for NM_000521.4(HEXB):c.1242G>A (p.Lys414=)]

NM_000521.4(HEXB):c.1242G>A (p.Lys414=)

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.1242G>A (p.Lys414=)

HGVS:

NC_000005.10:g.74718363G>A
NG_009770.2:g.83341G>A
NM_000521.4:c.1242G>AMANE SELECT
NM_001292004.2:c.567G>A
NP_000512.2:p.Lys414=
NP_001278933.1:p.Lys189=
NC_000005.9:g.74014188G>A
NM_000521.3:c.1242G>A

Links:

dbSNP: rs1309123671

NCBI 1000 Genomes Browser:

rs1309123671

Molecular consequence:

NM_000521.4:c.1242G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001292004.2:c.567G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000799611	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 1, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9475608, 23010210 Citation Link,
SCV002511535	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 19, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23010210, 29448188, 9475608 Citation Link,
SCV004293744	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23010210, 17576681, 9536098, 9475608, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000799611

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(May 1, 2018)

unknown

clinical testing

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

Citation Link,

SCV002511535

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 19, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004293744

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 5, 2023)

germline

clinical testing

PubMed (5)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype, phenotype and in silico pathogenicity analysis of HEXB mutations: Panel based sequencing for differential diagnosis of gangliosidosis.

Mahdieh N, Mikaeeli S, Tavasoli AR, Rezaei Z, Maleki M, Rabbani B.

Clin Neurol Neurosurg. 2018 Apr;167:43-53. doi: 10.1016/j.clineuro.2018.02.011. Epub 2018 Feb 8.

PubMed [citation]

PMID:: 29448188

Integrated multiplex ligation dependent probe amplification (MLPA) assays for the detection of alterations in the HEXB, GM2A and SMARCAL1 genes to support the diagnosis of Morbus Sandhoff, M. Tay-Sachs variant AB and Schimke immuno-osseous dysplasia in humans.

Sobek AK, Evers C, Dekomien G.

Mol Cell Probes. 2013 Feb;27(1):32-7. doi: 10.1016/j.mcp.2012.08.007. Epub 2012 Aug 27.

PubMed [citation]

PMID:: 23010210

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000799611.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511535.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: HEXB c.1242G>A (p.Lys414Lys) located at the last nucleotide of the exon alters a conserved nucleotide located adjacent to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. One predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon 10 skipping (example, Gomez-Lira_1998). The variant allele was found at a frequency of 4e-06 in 251298 control chromosomes. c.1242G>A has been reported in the literature as a homozygous and compound heterozygous genotype in at-least two individuals affected with Sandhoff Disease (example, Gomez-Lira_1998, Sobek_2012). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004293744.1

#	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 affects codon 414 of the HEXB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 9475608, 23010210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558077). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 and introduces a premature termination codon (PMID: 9475608). The resulting mRNA is expected to undergo nonsense-mediated decay. 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

Last Updated: Sep 29, 2024

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