VCV000046160.44 - ClinVar

NM_024422.6(DSC2):c.1073C>T (p.Thr358Ile)

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.

(17)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024422.6(DSC2):c.1073C>T (p.Thr358Ile)

Variation ID: 46160 Accession: VCV000046160.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 31082930 (GRCh38) [ NCBI UCSC ] 18: 28662896 (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	Feb 7, 2015	May 1, 2024	Jan 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024422.6:c.1073C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_077740.1:p.Thr358Ile	missense
NM_004949.5:c.1073C>T	NP_004940.1:p.Thr358Ile	missense
NC_000018.10:g.31082930G>A
NC_000018.9:g.28662896G>A
NG_008208.2:g.24496C>T
LRG_400:g.24496C>T
LRG_400t1:c.1073C>T
	Q02487:p.Thr358Ile

... more HGVS ... less HGVS

Protein change

T358I

Other names

Canonical SPDI

NC_000018.10:31082929:G:A

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.

0.00060 (A)

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

Exome Aggregation Consortium (ExAC) 0.00145

1000 Genomes Project 0.00060

Trans-Omics for Precision Medicine (TOPMed) 0.00090

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092

The Genome Aggregation Database (gnomAD) 0.00104

1000 Genomes Project 30x 0.00109

The Genome Aggregation Database (gnomAD), exomes 0.00133

Links

ClinGen: CA022394 UniProtKB: Q02487#VAR_062391 dbSNP: rs139399951 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.
DSC2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1575	1711

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/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Oct 26, 2020	RCV000039400.12
not provided	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 10, 2021	RCV000172527.13
Cardiac arrest	Likely benign (1)	no assertion criteria provided	Aug 26, 2014	RCV000157171.1
Arrhythmogenic right ventricular cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Dec 1, 2015	RCV000210891.3
Arrhythmogenic right ventricular dysplasia 11	Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV000228131.21
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Mar 23, 2018	RCV000243453.5
Cardiomyopathy	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Mar 9, 2018	RCV000770540.4

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 benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Not provided Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000051522.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 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: 3
Likely benign (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000290726.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Likely benign (Mar 23, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000319164.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 23861362‚ 24704780‚ 27153395 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Mar 17, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743494.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Likely benign (Jun 28, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744764.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Benign (Oct 26, 2020)	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: SCV001442580.1 First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020	Publications: PubMed (1) PubMed: 24704780 Comment: Variant summary: DSC2 c.1073C>T (p.Thr358Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: DSC2 c.1073C>T (p.Thr358Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250956 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016), strongly suggesting that the variant is benign. c.1073C>T has been reported in the literature in an individual with a possible diagnosis of arrhythmogenic cardiomyopathy (AC), however, two first-degree relatives carrying the variant, were unaffected, and there was no family history of AC (Rasmussen_2014). These authors also reported that patient derived keratinocytes expressed normal amount of the DSC2 protein, however, this does not allow conclusions about the variant effect on protein function (Rasmussen_2014). 12 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)
Likely benign (Mar 10, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610746.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Benign (Nov 28, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000901987.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Likely 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: SCV000903367.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Sep 04, 2017)	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: SCV000063084.4 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Publications: PubMed (2) PubMed: 27153395‚ 24704780 Comment: p.Thr358Ile in exon 8 of DSC2: This variant is not expected to have clinical sig nificance because it has been identified in 0.37% (94/25778) of … (more) p.Thr358Ile in exon 8 of DSC2: This variant is not expected to have clinical sig nificance because it has been identified in 0.37% (94/25778) of Finnish chromoso mes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http:/ /gnomAD.broadinstitute.org; dbSNP rs139399951). (less) Number of individuals with the variant: 3
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001281727.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 18678517 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811789.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Feb 10, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000516119.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 24704780, 18678517, 25351510, 27153395)
Likely benign (Dec 01, 2015)	criteria provided, single submitter (Amendola et al. (Genome Res. 2015)) Method: research	Arrhythmogenic right ventricular cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: CSER - NEXT Medicine variant annotation Accession: SCV000264600.1 First in ClinVar: Apr 25, 2016 Last updated: Apr 25, 2016 Comment: Found in patient having exome sequencing for an unrelated indication. No known history of Cardiomyopathy. .GERP=1.380.ExAC Alt Allele Frequencies=AFR:0.0098%,NFE:0.206%,EAS:0.0%,SAS:0.0%,FIN:0.353%,AMR:0.106%,OTH:0.227%.The variant was found in publications with … (more) Found in patient having exome sequencing for an unrelated indication. No known history of Cardiomyopathy. .GERP=1.380.ExAC Alt Allele Frequencies=AFR:0.0098%,NFE:0.206%,EAS:0.0%,SAS:0.0%,FIN:0.353%,AMR:0.106%,OTH:0.227%.The variant was found in publications with the following PMIDs:24704780; (less)
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: SCV001922235.1 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: SCV001955304.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (Aug 26, 2014)	no assertion criteria provided Method: clinical testing	Cardiac Arrest Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000206895.1 First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015	Number of individuals with the variant: 1
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Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant summary: DSC2 c.1073C>T (p.Thr358Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250956 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016), strongly suggesting that the variant is benign. c.1073C>T has been reported in the literature in an individual with a possible diagnosis of arrhythmogenic cardiomyopathy (AC), however, two first-degree relatives carrying the variant, were unaffected, and there was no family history of AC (Rasmussen_2014). These authors also reported that patient derived keratinocytes expressed normal amount of the DSC2 protein, however, this does not allow conclusions about the variant effect on protein function (Rasmussen_2014). 12 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.

Comment:

p.Thr358Ile in exon 8 of DSC2: This variant is not expected to have clinical sig nificance because it has been identified in 0.37% (94/25778) of Finnish chromoso mes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http:/ /gnomAD.broadinstitute.org; dbSNP rs139399951).

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely 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
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis.	Rasmussen TB	Circulation. Cardiovascular genetics	2014	PMID: 24704780
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362
A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy.	Posch MG	Molecular genetics and metabolism	2008	PMID: 18678517

Text-mined citations for rs139399951 ...

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_024422.6(DSC2):c.1073C>T (p.Thr358Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139399951 ...