NM_001943.5(DSG2):c.545A>G (p.Asn182Ser) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Mar 9, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000766579.3

Allele description [Variation Report for NM_001943.5(DSG2):c.545A>G (p.Asn182Ser)]

NM_001943.5(DSG2):c.545A>G (p.Asn182Ser)

Gene:
DSG2:desmoglein 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_001943.5(DSG2):c.545A>G (p.Asn182Ser)
HGVS:
  • NC_000018.10:g.31522104A>G
  • NG_007072.3:g.28863A>G
  • NM_001943.5:c.545A>GMANE SELECT
  • NP_001934.2:p.Asn182Ser
  • LRG_397t1:c.545A>G
  • LRG_397:g.28863A>G
  • NC_000018.9:g.29102067A>G
  • NM_001943.3:c.545A>G
  • NM_001943.4:c.545A>G
  • c.545A>G
Protein change:
N182S
Links:
dbSNP: rs368512832
NCBI 1000 Genomes Browser:
rs368512832
Molecular consequence:
  • NM_001943.5:c.545A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000518616GeneDxcriteria provided, single submitter
Uncertain significance
(Mar 9, 2021)
germlineclinical testing

Citation Link,

SCV000924769Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedUncertain significance
(May 13, 2016)
germlineprovider interpretation

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedprovider interpretation

Details of each submission

From GeneDx, SCV000518616.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Reported in association with DCM, including an African American female with infantile-onset DCM who harbored additional disease-related variants (Pugh et al., 2014; Walsh et al., 2017; Mazzarotto et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 44323; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31983221, 27532257, 24503780)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924769.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedprovider interpretationnot provided

Description

p.Asn182Ser (c.545A>G) in the DSG2 gene (NM_01943.3) We have seen this in one African-American adult with mild dilated cardiomyopathy and a family history suspicious for familial dilated cardiomyopathy. Given the frequency in the general population, the weak case data, the lack of conservation, and the poor match with the family’s phenotype, we consider this a variant of uncertain significance, probably benign. The variant has been seen in at least 1 unrelated case of dilated cardiomyopathy (DCM) (not including this patient's family). Pugh et al (2014) identified the variant in a female infant with a clinical diagnosis of DCM who was of “Black or African American” ethnicity. Variants in several other genes (TTN, DSP, MYH6, MYL3) were also identified in this patient. No family history or segregation data is available. Per the lab report: “The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In addition, the serine amino acid residue is found in multiple mammalian species, suggesting that this missense changes does not adversely affect protein function.” The variant was seen in 6 of ~60,000 individuals listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 3/10/16). The variant is seen in 5 out of 9798 (AF=0.0005103) African alleles and 1 out of 8612 (AF=0.0001161) East Asian alleles. No other variant at the same codon is listed in this database.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 23, 2021

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