VCV000039495.5 - ClinVar

NM_021815.5(SLC5A7):c.1497del (p.Lys499fs)

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.

(3)

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
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021815.5(SLC5A7):c.1497del (p.Lys499fs)

Variation ID: 39495 Accession: VCV000039495.5

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2q12.3 2: 108010615 (GRCh38) [ NCBI UCSC ] 2: 108627071 (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	Oct 10, 2016	Oct 8, 2024	Nov 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021815.5:c.1497del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068587.1:p.Lys499fs	frameshift
NM_001305005.3:c.1497del	NP_001291934.1:p.Lys499fs	frameshift
NM_001305006.3:c.1182del	NP_001291935.1:p.Lys394fs	frameshift
NM_001305007.3:c.756del	NP_001291936.1:p.Lys252fs	frameshift
NM_021815.4:c.1497delG
NC_000002.12:g.108010615del
NC_000002.11:g.108627071del
NG_042267.1:g.29102del

... more HGVS ... less HGVS

Protein change

K252fs, K394fs, K499fs

Other names

Canonical SPDI

NC_000002.12:108010614:G:

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.

Links

OMIM: 608761.0001 dbSNP: rs1558872865 VarSome

Comment on variant

ClinGen staff contributed the HGVS expression for this variant.

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.
SLC5A7		-	-	GRCh38 GRCh37	496	542

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.
Neuronopathy, distal hereditary motor, type 7A	Pathogenic (1)	no assertion criteria provided	Dec 7, 2012	RCV000032691.5
Charcot-Marie-Tooth disease	Uncertain significance (1)	no assertion criteria provided	-	RCV000790226.1
SLC5A7-related disorder	Likely pathogenic (1)	no assertion criteria provided	Nov 6, 2023	RCV003894840.2

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.
Pathogenic (Dec 07, 2012)	no assertion criteria provided Method: literature only	NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 7 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056454.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023	Publications: PubMed (3) PubMed: 7420092‚ 11294660‚ 23141292 Comment on evidence: In affected members of a large multigenerational Welsh family with autosomal dominant distal hereditary motor neuronopathy-7 (HMND7; 158580) reported by Young and Harper (1980) and … (more) In affected members of a large multigenerational Welsh family with autosomal dominant distal hereditary motor neuronopathy-7 (HMND7; 158580) reported by Young and Harper (1980) and McEntagart et al. (2001), Barwick et al. (2012) identified a heterozygous 1-bp deletion (c.1497delG) in the SLC5A7 gene, resulting in a frameshift and premature termination (Lys499AsnfsTer13). The truncated protein would lack the transporter's final 82 residues of the conserved cytoplasmic C terminus, which is known to regulate surface transporter trafficking. The mutation, which was identified by exome sequencing and segregated with the disorder in this family, was not found in genomic databases. In vitro functional expression assays showed that the mutation resulted in reduced protein levels and reduced choline transport due to a decrease in Vmax. When the mutant and wildtype cDNAs were coexpressed, the combined levels of the transporters were reduced to about 30%, indicating that the mutation exerts a dominant-negative effect. Patient cells showed barely detectable choline transport activity, again consistent with a dominant-negative effect as opposed to haploinsufficiency. The phenotype was characterized by onset in the second decade of nonfatiguing progressive distal muscle wasting and weakness associated with vocal cord paresis due to involvement of the tenth cranial nerve. Given the role of SLC5A7 at the neuromuscular junction (NMJ), Barwick et al. (2012) commented on the lack of features usually associated with congenital myasthenic syndromes (see, e.g., 608931), which are caused by mutations in genes involved in synaptic transmission at the NMJ. (less)
Uncertain significance (-)	no assertion criteria provided Method: literature only	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000929618.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Publications: PubMed (1) PubMed: 23141292
Likely pathogenic (Nov 06, 2023)	no assertion criteria provided Method: clinical testing	SLC5A7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004712964.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The SLC5A7 c.1497delG variant is predicted to result in a frameshift and premature protein termination (p.Lys499Asnfs13). This variant was reported to segregate with several affected … (more) The SLC5A7 c.1497delG variant is predicted to result in a frameshift and premature protein termination (p.Lys499Asnfs13). This variant was reported to segregate with several affected individuals in a large family with hereditary motor neuropathy, type VII (Barwick et al 2012. PubMed ID: 23141292). This variant occurs in the last exon of the SLC5A7 gene and likely escapes nonsense-mediated decay and functional studies indicate a dominant-negative impact (Barwick et al 2012. PubMed ID: 23141292). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Other frameshift variants in the last exon of SLC5A7 have been reported to be pathogenic for autosomal dominant hereditary motor neuropathy (Salter et al. 2018. PubMed ID: 29582019). This variant is interpreted as likely pathogenic. (less)

Comment:

The SLC5A7 c.1497delG variant is predicted to result in a frameshift and premature protein termination (p.Lys499Asnfs*13). This variant was reported to segregate with several affected individuals in a large family with hereditary motor neuropathy, type VII (Barwick et al 2012. PubMed ID: 23141292). This variant occurs in the last exon of the SLC5A7 gene and likely escapes nonsense-mediated decay and functional studies indicate a dominant-negative impact (Barwick et al 2012. PubMed ID: 23141292). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Other frameshift variants in the last exon of SLC5A7 have been reported to be pathogenic for autosomal dominant hereditary motor neuropathy (Salter et al. 2018. PubMed ID: 29582019). This variant is interpreted as likely pathogenic.

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
Defective presynaptic choline transport underlies hereditary motor neuropathy.	Barwick KE	American journal of human genetics	2012	PMID: 23141292
Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14.	McEntagart M	American journal of human genetics	2001	PMID: 11294660
Hereditary distal spinal muscular atrophy with vocal cord paralysis.	Young ID	Journal of neurology, neurosurgery, and psychiatry	1980	PMID: 7420092

Text-mined citations for rs1558872865 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_021815.5(SLC5A7):c.1497del (p.Lys499fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1558872865 ...