VCV000036015.25 - ClinVar

NM_004415.4(DSP):c.1dup (p.Met1fs)

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.

(16)

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
Uncertain significance(1); Benign(12)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004415.4(DSP):c.1dup (p.Met1fs)

Variation ID: 36015 Accession: VCV000036015.25

Type and length

Duplication, 1 bp

Location

Cytogenetic: 6p24.3 6: 7541915-7541916 (GRCh38) [ NCBI UCSC ] 6: 7542149 (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	Jun 4, 2015	Jun 10, 2023	Sep 23, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_004415.4:c.1dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004406.2:p.Met1fs
NM_004415.4:c.1dupA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001008844.3:c.1dup	NP_001008844.1:p.Met1fs
NM_001319034.2:c.1dup	NP_001305963.1:p.Met1fs
NC_000006.12:g.7541916dup
NC_000006.11:g.7542149dup
NG_008803.1:g.5280dup
LRG_423:g.5280dup
LRG_423t1:c.1dup

... more HGVS ... less HGVS

Protein change

M1fs

Other names

p.?

Canonical SPDI

NC_000006.12:7541915:A:AA

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.

0.19968 (AA)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.16650

The Genome Aggregation Database (gnomAD), exomes 0.16713

The Genome Aggregation Database (gnomAD) 0.17362

Trans-Omics for Precision Medicine (TOPMed) 0.17715

Exome Aggregation Consortium (ExAC) 0.19939

1000 Genomes Project 0.19968

1000 Genomes Project 30x 0.20003

Links

ClinGen: CA282478 dbSNP: rs17133512 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.
DSP		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4747	4961
DSP-AS1	-	-	-	GRCh38	-	189

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.
not specified	Benign (8)	criteria provided, multiple submitters, no conflicts	Apr 24, 2019	RCV000037982.24
Lethal acantholytic epidermolysis bullosa	Benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000389020.5
Arrhythmogenic right ventricular cardiomyopathy	Benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000292424.5
Woolly hair-skin fragility syndrome	Benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000346732.5
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 22, 2015	RCV000622220.1
Cardiomyopathy	Benign (2)	criteria provided, multiple submitters, no conflicts	Sep 23, 2022	RCV000771055.4
not provided	Benign (1)	criteria provided, single submitter	-	RCV000845351.6
Arrhythmogenic right ventricular dysplasia 8	Uncertain significance (1)	criteria provided, single submitter	Sep 26, 2016	RCV001253578.1

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987399.1 First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019
Uncertain significance (Sep 26, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 8 Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429369.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020	Number of individuals with the variant: 1
Benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	not specified Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000055160.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 108
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310350.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Epidermolysis Bullosa, Lethal Acantholytic Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000464814.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Skin Fragility-Woolly Hair Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000464816.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Cardiomyopathy, ARVC Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000464815.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Sep 20, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000233556.4 First in ClinVar: Jul 05, 2015 Last updated: Jun 10, 2023	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Mar 09, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000902564.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (May 03, 2010)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061648.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Publications: PubMed (2) PubMed: 10395892‚ 18632414 Comment: The variant has been reported in dbSNP without frequency information (rs17133512 ). Classified as benign based on high allele frequency (0.162, n=290 chromosomes ) in … (more) The variant has been reported in dbSNP without frequency information (rs17133512 ). Classified as benign based on high allele frequency (0.162, n=290 chromosomes ) in ARVC probands tested at the LMM. In addition, the fraction of probands carr ying the -1_1insA variant matches the expected detection rate for ARVC (~50%), f urther supporting a benign role. (less) Number of individuals with the variant: 577
Benign (Apr 24, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052326.4 First in ClinVar: Apr 04, 2013 Last updated: Nov 08, 2019	Publications: PubMed (1) PubMed: 18632414 Comment: Variant summary: DSP c.1dupA is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of … (more) Variant summary: DSP c.1dupA is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.17 in 231420 control chromosomes in the gnomAD database, including 3569 homozygotes. The observed variant frequency is approximately 6685.078 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1dupA has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Dec 22, 2015)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000734861.3 First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018	Comment: Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance Number of individuals with the variant: 1
Benign (Sep 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003802956.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923039.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953018.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972469.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

The variant has been reported in dbSNP without frequency information (rs17133512 ). Classified as benign based on high allele frequency (0.162, n=290 chromosomes ) in ARVC probands tested at the LMM. In addition, the fraction of probands carr ying the -1_1insA variant matches the expected detection rate for ARVC (~50%), f urther supporting a benign role.

Comment:

Variant summary: DSP c.1dupA is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.17 in 231420 control chromosomes in the gnomAD database, including 3569 homozygotes. The observed variant frequency is approximately 6685.078 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1dupA has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as 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
Arrhythmogenic right ventricular dysplasia: clinical characteristics and identification of novel desmosome gene mutations.	Yu CC	Journal of the Formosan Medical Association = Taiwan yi zhi	2008	PMID: 18632414
Initiation of translation in prokaryotes and eukaryotes.	Kozak M	Gene	1999	PMID: 10395892

Text-mined citations for rs17133512 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_004415.4(DSP):c.1dup (p.Met1fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs17133512 ...