ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.961T>A (p.Phe321Ile)
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.961T>A (p.Phe321Ile)
Variation ID: 252596 Accession: VCV000252596.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31524835 (GRCh38) [ NCBI UCSC ] 18: 29104798 (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 Aug 1, 2016 Apr 20, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.961T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Phe321Ile missense NC_000018.10:g.31524835T>A NC_000018.9:g.29104798T>A NG_007072.3:g.31594T>A LRG_397:g.31594T>A LRG_397t1:c.961T>A - Protein change
- F321I
- Other names
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- Canonical SPDI
- NC_000018.10:31524834:T:A
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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 |
1092 | 1881 |
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
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
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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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Dec 18, 2023 | RCV000238845.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 18, 2017 | RCV000426540.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 8, 2023 | RCV001184545.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV001234222.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 1, 2022 | RCV002374407.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 18, 2021 | RCV002503921.1 |
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
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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
(Apr 18, 2017)
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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: SCV000520832.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The F321I variant of uncertain significance in the DSG2 gene has previously been reported in one individual meeting diagnostic criteria for ARVC, however, family history … (more)
The F321I variant of uncertain significance in the DSG2 gene has previously been reported in one individual meeting diagnostic criteria for ARVC, however, family history and segregation data was not provided (Xu et al., 2010). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the F321I variant. Furthermore, the F321I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. (less)
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Uncertain significance
(Jul 01, 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: SCV002690662.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.F321I variant (also known as c.961T>A), located in coding exon 8 of the DSG2 gene, results from a T to A substitution at nucleotide … (more)
The p.F321I variant (also known as c.961T>A), located in coding exon 8 of the DSG2 gene, results from a T to A substitution at nucleotide position 961. The phenylalanine at codon 321 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort and in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97; Lopes LR et al. Heart, 2015 Feb;101:294-301). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Oct 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000297110.3
First in ClinVar: Aug 01, 2016 Last updated: Dec 24, 2022 |
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Uncertain significance
(Aug 18, 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: SCV002816012.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Nov 29, 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: SCV001406855.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 321 of the DSG2 protein (p.Phe321Ile). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 321 of the DSG2 protein (p.Phe321Ile). This variant is present in population databases (rs201040643, gnomAD 0.005%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). ClinVar contains an entry for this variant (Variation ID: 252596). 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. 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. (less)
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Uncertain significance
(Feb 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001350554.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces phenylalanine with isoleucine at codon 321 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces phenylalanine with isoleucine at codon 321 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals arrhythmogenic right ventricular cardiomyopathy (PMID: 28471438). This variant has been identified in 6/280820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004819497.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces phenylalanine with isoleucine at codon 321 of the DSG2 protein. Computational prediction tools and conservation analyses suggest that this variant may … (more)
This missense variant replaces phenylalanine with isoleucine at codon 321 of the DSG2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two individuals arrhythmogenic right ventricular cardiomyopathy (PMID: 28471438). This variant has also been identified in 6/280820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 9
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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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Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. | Ye JZ | Clinical genetics | 2019 | PMID: 31402444 |
Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. | Haggerty CM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28471438 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Text-mined citations for rs201040643 ...
HelpRecord last updated Apr 20, 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.