VCV000056557.10 - ClinVar

NM_012434.5(SLC17A5):c.719G>A (p.Trp240Ter)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012434.5(SLC17A5):c.719G>A (p.Trp240Ter)

Variation ID: 56557 Accession: VCV000056557.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q13 6: 73635482 (GRCh38) [ NCBI UCSC ] 6: 74345205 (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	Jul 24, 2013	Jun 17, 2024	Feb 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_012434.5:c.719G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036566.1:p.Trp240Ter	nonsense
NC_000006.12:g.73635482C>T
NC_000006.11:g.74345205C>T
NG_008272.1:g.23533G>A

Protein change

W240*

Other names

Canonical SPDI

NC_000006.12:73635481:C:T

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

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00005

Exome Aggregation Consortium (ExAC) 0.00010

Links

ClinGen: CA263928 dbSNP: rs386833993 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.
SLC17A5		-	-	GRCh38 GRCh37	566	663

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.
Salla disease	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 28, 2024	RCV000049970.11

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.
Likely pathogenic (Nov 27, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Salla disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918211.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (1) PubMed: 10947946 Comment: Variant summary: The SLC17A5 c.719G>A (p.Trp240X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC17A5 protein due to nonsense … (more) Variant summary: The SLC17A5 c.719G>A (p.Trp240X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC17A5 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 13/237362 control chromosomes at a frequency of 0.0000548, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC17A5 variant (0.0023717). The variant has been reported in at least one affected individual in the literature (Aula_2000). In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic. (less)
Pathogenic (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Salla disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002027576.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021
Pathogenic (Feb 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Salla disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201202.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Salla disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000937248.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 10947946‚ 10581036‚ 15172001 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56557). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56557). This premature translational stop signal has been observed in individual(s) with sialic acid-storage disease (PMID: 10947946). This variant is present in population databases (rs386833993, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Trp240*) in the SLC17A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC17A5 are known to be pathogenic (PMID: 10581036, 10947946, 15172001). (less)
probable-pathogenic (-)	no assertion criteria provided Method: not provided	Salla disease Affected status: not provided Allele origin: not provided	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000082379.1 First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013 Comment: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference	Comment: Converted during submission to Likely pathogenic.

Comment:

Variant summary: The SLC17A5 c.719G>A (p.Trp240X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC17A5 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 13/237362 control chromosomes at a frequency of 0.0000548, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC17A5 variant (0.0023717). The variant has been reported in at least one affected individual in the literature (Aula_2000). In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56557). This premature translational stop signal has been observed in individual(s) with sialic acid-storage disease (PMID: 10947946). This variant is present in population databases (rs386833993, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Trp240*) in the SLC17A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC17A5 are known to be pathogenic (PMID: 10581036, 10947946, 15172001).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity.	Kleta R	Molecular genetics and metabolism	2004	PMID: 15172001
The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation.	Aula N	American journal of human genetics	2000	PMID: 10947946
A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases.	Verheijen FW	Nature genetics	1999	PMID: 10581036

Text-mined citations for rs386833993 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_012434.5(SLC17A5):c.719G>A (p.Trp240Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386833993 ...