NM_000521.4(HEXB):c.170G>A (p.Trp57Ter) AND Sandhoff disease

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 27, 2022
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:: RCV000491131.4

Allele description

NM_000521.4(HEXB):c.170G>A (p.Trp57Ter)

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.170G>A (p.Trp57Ter)

HGVS:

NC_000005.10:g.74685430G>A
NG_009770.2:g.50408G>A
NM_000521.4:c.170G>AMANE SELECT
NM_001292004.2:c.-376-3898G>A
NP_000512.2:p.Trp57Ter
NC_000005.9:g.73981255G>A
NM_000521.3:c.170G>A

Protein change:

W57*

Links:

dbSNP: rs1114167287

NCBI 1000 Genomes Browser:

rs1114167287

Molecular consequence:

NM_001292004.2:c.-376-3898G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000521.4:c.170G>A - nonsense - [Sequence Ontology: SO:0001587]

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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Melanogaster sp. 'CA02' isolate CA FUNDIS iNaturalist # 153890784 small subunit ...
Melanogaster sp. 'CA02' isolate CA FUNDIS iNaturalist # 153890784 small subunit ribosomal RNA gene, partial sequence; internal transcribed spacer 1, 5.8S ribosomal RNA gene, and internal transcribed spacer 2, complete sequence; and large subunit ribosomal RNA gene, partial sequence
gi|2678068977|gb|PP357278.1|

Nucleotide
PREDICTED: Gallus gallus piccolo presynaptic cytomatrix protein (PCLO), transcri...
PREDICTED: Gallus gallus piccolo presynaptic cytomatrix protein (PCLO), transcript variant X5, mRNA
gi|2201562084|ref|XM_040665439.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000282195	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine - The combination of WES, CNV-derived from WES, paralog studies, and GeneMatcher provide potential molecular diagnosis in a cohort from Saudi Arabia	no assertion criteria provided	Pathogenic (Jan 10, 2016)	inherited	research
SCV002600744	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003525833	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 23, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27435318, 7550345, 18758829, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000282195

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine - The combination of WES, CNV-derived from WES, paralog studies, and GeneMatcher provide potential molecular diagnosis in a cohort from Saudi Arabia

no assertion criteria provided

Pathogenic
(Jan 10, 2016)

inherited

research

SCV002600744

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Oct 27, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV003525833

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 23, 2022)

germline

clinical testing

PubMed (4)
[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	inherited	yes	1	not provided	not provided	not provided	no	research

Citations

PubMed

Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate.

Charng WL, Karaca E, Coban Akdemir Z, Gambin T, Atik MM, Gu S, Posey JE, Jhangiani SN, Muzny DM, Doddapaneni H, Hu J, Boerwinkle E, Gibbs RA, Rosenfeld JA, Cui H, Xia F, Manickam K, Yang Y, Faqeih EA, Al Asmari A, Saleh MA, El-Hattab AW, et al.

BMC Med Genomics. 2016 Jul 19;9(1):42. doi: 10.1186/s12920-016-0208-3.

PubMed [citation]

PMID:: 27435318
PMCID:: PMC4950750

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

See all PubMed Citations (4)

Details of each submission

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine - The combination of WES, CNV-derived from WES, paralog studies, and GeneMatcher provide potential molecular diagnosis in a cohort from Saudi Arabia, SCV000282195.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	no	research	not provided

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600744.1

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

Description

Variant summary: HEXB c.170G>A (p.Trp57X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 225874 control chromosomes. c.170G>A has been reported in the literature in a homozygous patient with neurological disease (Charng_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as 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 Invitae, SCV003525833.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 242876). This premature translational stop signal has been observed in individual(s) with HEXB-related conditions (PMID: 27435318). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp57*) 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).

#	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: Feb 14, 2024

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