VCV000126510.42 - ClinVar

NM_000520.4(HEXA):c.745C>T (p.Arg249Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity; other
Uncertain significance(1); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000520.4(HEXA):c.745C>T (p.Arg249Trp)

Variation ID: 126510 Accession: VCV000126510.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 72350578 (GRCh38) [ NCBI UCSC ] 15: 72642919 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 14, 2015	Dec 22, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000520.6:c.745C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000511.2:p.Arg249Trp	missense
NM_001318825.2:c.778C>T	NP_001305754.1:p.Arg260Trp	missense
NR_134869.3:n.787C>T		non-coding transcript variant
NC_000015.10:g.72350578G>A
NC_000015.9:g.72642919G>A
NG_009017.2:g.30602C>T
	P06865:p.Arg249Trp

... more HGVS ... less HGVS

Protein change

R249W, R260W

Other names

Canonical SPDI

NC_000015.10:72350577:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on catalytic protein function; Variation Ontology [ VariO:0008]

reduced; Variation Ontology [ VariO:0290]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00019

The Genome Aggregation Database (gnomAD), exomes 0.00019

Exome Aggregation Consortium (ExAC) 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00025

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Links

ClinGen: CA276005 Genetic Testing Registry (GTR): GTR000321634 UniProtKB: P06865#VAR_003220 dbSNP: rs138058578 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HEXA		-	-	GRCh38 GRCh37	1145	1179

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Tay-Sachs disease	other (2)	criteria provided, multiple submitters, no conflicts	Dec 13, 2018	RCV000190592.16
not provided	Conflicting interpretations of pathogenicity; other (3)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000375852.22

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
other (May 30, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Tay-Sachs disease Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Study: CSER-MedSeq Accession: SCV000245618.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015	Publications: PubMed (3) PubMed: 1384323‚ 24498621‚ 7902672 Comment: pseudodeficiency Number of individuals with the variant: 1
other pseudodeficiency allele (Dec 13, 2018)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000933533.1 First in ClinVar: Aug 14, 2019 Last updated: Aug 14, 2019
Uncertain significance (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004698536.9 First in ClinVar: Mar 10, 2024 Last updated: Dec 22, 2024	Comment: HEXA: PM2:Supporting Number of individuals with the variant: 1
Benign (Aug 11, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697174.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (3) PubMed: 7717398‚ 7902672‚ 9169471 Comment: Variant summary: The HEXA c.745C>T (p.Arg249Trp) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The … (more) Variant summary: The HEXA c.745C>T (p.Arg249Trp) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 28/121408 (1/4336), which does not exceed the estimated maximal expected allele frequency for a pathogenic HEXA variant of 1/715. The variant of interest is known to be a common pseudodeficiency allele, which is not associated with neurologic disease but is associated wtih reduced degradation of the synthetic substrate when HEX A enzymatic activity is determined (Gene Reviews). Therefore, the variant of interest is classified as Benign. (less)
other (Jul 19, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331536.3 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed

Comment:

Variant summary: The HEXA c.745C>T (p.Arg249Trp) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 28/121408 (1/4336), which does not exceed the estimated maximal expected allele frequency for a pathogenic HEXA variant of 1/715. The variant of interest is known to be a common pseudodeficiency allele, which is not associated with neurologic disease but is associated wtih reduced degradation of the synthetic substrate when HEX A enzymatic activity is determined (Gene Reviews). Therefore, the variant of interest is classified as Benign.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on catalytic protein function (VariO:0008) reduced (VariO:0290)			Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Study: CSER-MedSeq Accession: SCV000245618.1	Publications PubMed (3)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening.	Hoffman JD	Molecular genetics & genomic medicine	2013	PMID: 24498621
Benign HEXA mutations, C739T(R247W) and C745T(R249W), cause beta-hexosaminidase A pseudodeficiency by reducing the alpha-subunit protein levels.	Cao Z	The Journal of biological chemistry	1997	PMID: 9169471
Mutational analyses of Tay-Sachs disease: studies on Tay-Sachs carriers of French Canadian background living in New England.	Triggs-Raine B	American journal of human genetics	1995	PMID: 7717398
A second mutation associated with apparent beta-hexosaminidase A pseudodeficiency: identification and frequency estimation.	Cao Z	American journal of human genetics	1993	PMID: 7902672
A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.	Triggs-Raine BL	American journal of human genetics	1992	PMID: 1384323
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA	-	-	-	-

Text-mined citations for rs138058578 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 04, 2025

ClinVar Genomic variation as it relates to human health

NM_000520.4(HEXA):c.745C>T (p.Arg249Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138058578 ...