ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.581C>T (p.Ser194Leu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001943.5(DSG2):c.581C>T (p.Ser194Leu)
Variation ID: 44324 Accession: VCV000044324.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31522140 (GRCh38) [ NCBI UCSC ] 18: 29102103 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 9, 2018 Feb 20, 2024 Jul 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.581C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Ser194Leu missense NC_000018.10:g.31522140C>T NC_000018.9:g.29102103C>T NG_007072.3:g.28899C>T LRG_397:g.28899C>T LRG_397t1:c.581C>T - Protein change
- S194L
- Other names
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- Canonical SPDI
- NC_000018.10:31522139:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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DSG2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1016 | 1760 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2022 | RCV000037312.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 18, 2023 | RCV000642313.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2019 | RCV001560109.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 16, 2022 | RCV003162323.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 21, 2021 | RCV002482987.1 |
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
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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
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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
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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. |
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Uncertain significance
(May 27, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060969.4
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Ser194Leu variant in DSG2 has been reported in a compound heterozygous ind ividual with ARVC (Nakajima 2012). In addition, this variant has been identified … (more)
The p.Ser194Leu variant in DSG2 has been reported in a compound heterozygous ind ividual with ARVC (Nakajima 2012). In addition, this variant has been identified by our laboratory in one child with clinical features of DCM and ARVD/C. It has been identified in 3/16492 South Asian chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs374875442). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the p.Ser194Leu variant is u ncertain. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Oct 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001782450.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Reported with a different missense variant on the opposite allele (in trans) in an individual with ARVC, and observed in apparent homozygous state in another … (more)
Reported with a different missense variant on the opposite allele (in trans) in an individual with ARVC, and observed in apparent homozygous state in another individual with ARVC in published literature (Nakajima et al., 2012; Shapieva et al., 2014); in one family, S194L segregated in an unaffected relative and a relative whose echocardiogram showed a minor right ventricular structural abnormality, but their EKG was not suggestive of ARVC (Nakajima et al., 2012); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 44324; Landrum et al., 2016), and one clinical laboratory identified this variant in a child with clinical features of DCM and ARVC (SCV000060969.4; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30177324, 22214898, 23299917) (less)
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Uncertain significance
(Dec 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003858254.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.S194L variant (also known as c.581C>T), located in coding exon 6 of the DSG2 gene, results from a C to T substitution at nucleotide … (more)
The p.S194L variant (also known as c.581C>T), located in coding exon 6 of the DSG2 gene, results from a C to T substitution at nucleotide position 581. The serine at codon 194 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts; however, clinical details were limited and additional alterations in other ARVC-related genes were identified in one case (Nakajima T et al. Circ J, 2012 Dec;76:737-43; Ren C et al. Medicine (Baltimore), 2020 Jun;99:e20279). Additionally, this alteration was detected in a left ventricular non-compaction (LVNC) cohort; however, clinical details were also limited (Mazzarotto F et al. Genet Med, 2021 May;23:856-864). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Apr 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511640.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: DSG2 c.581C>T (p.Ser194Leu) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of … (more)
Variant summary: DSG2 c.581C>T (p.Ser194Leu) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.581C>T has been reported in the literature in compound heterozygosity with another DSG2 variant in an individual with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVC) (example, Nakajima_2012). Her asymptomatic sibling and mother carried this variant. A minor structural abnormality was noted upon echocardiographic examination of the mother. The authors suggested that this variant alone may not be sufficiently penetrant to cause ARVC. Since this report, it has also been reported in one case of left ventricular noncompaction (LVNC) (example, Mazzarotto_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jul 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 10
Dilated cardiomyopathy 1BB
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002792838.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jul 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 10
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000763982.4
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 44324). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 22214898, 33500567). This variant is present in population databases (rs374875442, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 194 of the DSG2 protein (p.Ser194Leu). (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. | Mazzarotto F | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33500567 |
Congenital heart disease combined with Arrhythmogenic Right Ventricular Cardiomyopathy: A CARE compliant case report and literature review. | Ren C | Medicine | 2020 | PMID: 32569162 |
In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns. | Debus JD | Journal of molecular and cellular cardiology | 2019 | PMID: 30885746 |
Compound and heterozygous mutations of DSG2 identified by Whole Exome Sequencing in arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular tachycardia. | Lin Y | Journal of electrocardiology | 2018 | PMID: 30177324 |
Compound and digenic heterozygosity in desmosome genes as a cause of arrhythmogenic right ventricular cardiomyopathy in Japanese patients. | Nakajima T | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22214898 |
Text-mined citations for rs374875442 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.