NM_000521.4(HEXB):c.1294dup (p.Glu432fs) AND Sandhoff disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 10, 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:: RCV001056488.11

Allele description [Variation Report for NM_000521.4(HEXB):c.1294dup (p.Glu432fs)]

NM_000521.4(HEXB):c.1294dup (p.Glu432fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

5q13.3

Genomic location:

Preferred name:

NM_000521.4(HEXB):c.1294dup (p.Glu432fs)

HGVS:

NC_000005.10:g.74718848dup
NG_009770.2:g.83826dup
NM_000521.4:c.1294dupMANE SELECT
NM_001292004.2:c.619dup
NP_000512.2:p.Glu432fs
NP_001278933.1:p.Glu207fs
NC_000005.9:g.74014671_74014672insG
NC_000005.9:g.74014673dup
NM_000521.3:c.1294dup
NM_000521.3:c.1294dupG
NM_000521.4:c.1294dupGMANE SELECT

Protein change:

E207fs

Links:

dbSNP: rs775920504

NCBI 1000 Genomes Browser:

rs775920504

Molecular consequence:

NM_000521.4:c.1294dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001292004.2:c.619dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001220931	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7550345, 18758829, 28492532
SCV002793481	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 4, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003845013	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 10, 2024)	germline	clinical testing	Citation Link,
SCV004040844	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 18, 2023)	unknown	clinical testing	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism.

Sango K, Yamanaka S, Hoffmann A, Okuda Y, Grinberg A, Westphal H, McDonald MP, Crawley JN, Sandhoff K, Suzuki K, Proia RL.

Nat Genet. 1995 Oct;11(2):170-6.

PubMed [citation]

PMID:: 7550345

Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles.

Zampieri S, Filocamo M, Buratti E, Stroppiano M, Vlahovicek K, Rosso N, Bignulin E, Regis S, Carnevale F, Bembi B, Dardis A.

Neurogenetics. 2009 Feb;10(1):49-58. doi: 10.1007/s10048-008-0145-1. Epub 2008 Aug 29.

PubMed [citation]

PMID:: 18758829

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001220931.5

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

Description

This sequence change creates a premature translational stop signal (p.Glu432Glyfs*4) in the HEXB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). This variant is present in population databases (rs775920504, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with HEXB-related conditions. ClinVar contains an entry for this variant (Variation ID: 851972). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Fulgent Genetics, Fulgent Genetics, SCV002793481.1

#	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	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, SCV003845013.2

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

Description

Variant summary: HEXB c.1294dupG (p.Glu432GlyfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 251418 control chromosomes. To our knowledge, no occurrence of c.1294dupG in individuals affected with Sandhoff Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 851972). 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 Baylor Genetics, SCV004040844.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 18, 2024

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