NM_000521.4(HEXB):c.1417+5G>A AND Sandhoff disease

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 8, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000673197.5

Allele description [Variation Report for NM_000521.4(HEXB):c.1417+5G>A]

NM_000521.4(HEXB):c.1417+5G>A

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.1417+5G>A

HGVS:

NC_000005.10:g.74718976G>A
NG_009770.2:g.83954G>A
NM_000521.4:c.1417+5G>AMANE SELECT
NM_001292004.2:c.742+5G>A
NC_000005.9:g.74014801G>A
NM_000521.3:c.1417+5G>A

Links:

dbSNP: rs763517499

NCBI 1000 Genomes Browser:

rs763517499

Molecular consequence:

NM_000521.4:c.1417+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001292004.2:c.742+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV000798373	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Mar 8, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17237499, 20926324 Citation Link,
SCV004174818	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000798373

Counsyl

criteria provided, single submitter

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

Uncertain significance
(Mar 8, 2018)

unknown

clinical testing

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

Citation Link,

SCV004174818

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 8, 2023)

germline

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	germline	yes	1	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

Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis.

Maegawa GH, Tropak M, Buttner J, Stockley T, Kok F, Clarke JT, Mahuran DJ.

J Biol Chem. 2007 Mar 23;282(12):9150-61. Epub 2007 Jan 21.

PubMed [citation]

PMID:: 17237499
PMCID:: PMC1851921

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants).

Clarke JT, Mahuran DJ, Sathe S, Kolodny EH, Rigat BA, Raiman JA, Tropak MB.

Mol Genet Metab. 2011 Jan;102(1):6-12. doi: 10.1016/j.ymgme.2010.09.004. Epub 2010 Sep 17.

PubMed [citation]

PMID:: 20926324
PMCID:: PMC3019177

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000798373.1

#	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV004174818.1

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

Description

A heterozygous 5’ splice site variant in intron 11 of the HEXB gene was detected. The observed variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.0016% in the gnomAD database. The in-silico prediction of the variant is disease causing by MutationTaster2 and SpliceAI. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic.

#	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

Last Updated: Oct 20, 2024

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