VCV003065995.2 - ClinVar

NM_022834.5(VWA1):c.462del (p.Met155fs)

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.

(2)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022834.5(VWA1):c.462del (p.Met155fs)

Variation ID: 3065995 Accession: VCV003065995.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 1p36.33 1: 1437309 (GRCh38) [ NCBI UCSC ] 1: 1372689 (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	Apr 6, 2024	Jul 23, 2024	Jul 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_022834.5:c.462del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_073745.2:p.Met155fs	frameshift
NM_022834.5:c.462delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NM_022834.4:c.462delC
NM_199121.3:c.74-7del		intron variant
NC_000001.11:g.1437315del
NC_000001.10:g.1372695del

... more HGVS ... less HGVS

Protein change

M155fs

Other names

Canonical SPDI

NC_000001.11:1437308:CCCCCCC:CCCCCC

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

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.
VWA1		-	-	GRCh38 GRCh37	91	246

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, autosomal recessive 7	Pathogenic (2)	criteria provided, single submitter	Jul 17, 2023	RCV003989450.2

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 (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 7 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005087217.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 33459760‚ 33559681 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuropathy, hereditary motor, with myopathic features (MIM#619216). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Features and age of onset varied substantially (PMID: 33459760). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). This truncation will result in sequence change of the final third of the VWA domain as well as complete loss of both fn3 domains, one of which is within a very highly constrained region (DECIPHER). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three variants predicted to result in a truncated protein located downstream have been reported likely pathogenic and pathogenic (ClinVar, PMID: 33459760). (SP) 0803 - This variant has limited previous evidence of pathogenicity. It has been detected in two homozygous individuals with hereditary motor neuropathy from a multigenerational consanguineous Afghan family (PMID: 33559681). (SP) 0903 - This variant has limited evidence for segregation with disease. It is homozygous in two affected individuals and three unaffected individuals were confirmed carriers in a consanguineous family (PMID: 33559681). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Nov 22, 2022)	no assertion criteria provided Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 7 Affected status: yes Allele origin: biparental	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV004808320.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuropathy, hereditary motor, with myopathic features (MIM#619216). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Features and age of onset varied substantially (PMID: 33459760). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). This truncation will result in sequence change of the final third of the VWA domain as well as complete loss of both fn3 domains, one of which is within a very highly constrained region (DECIPHER). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three variants predicted to result in a truncated protein located downstream have been reported likely pathogenic and pathogenic (ClinVar, PMID: 33459760). (SP) 0803 - This variant has limited previous evidence of pathogenicity. It has been detected in two homozygous individuals with hereditary motor neuropathy from a multigenerational consanguineous Afghan family (PMID: 33559681). (SP) 0903 - This variant has limited evidence for segregation with disease. It is homozygous in two affected individuals and three unaffected individuals were confirmed carriers in a consanguineous family (PMID: 33559681). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.	Pagnamenta AT	Brain : a journal of neurology	2021	PMID: 33559681
Bi-allelic truncating mutations in VWA1 cause neuromyopathy.	Deschauer M	Brain : a journal of neurology	2021	PMID: 33459760

Text-mined citations for this variant ...

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_022834.5(VWA1):c.462del (p.Met155fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...