ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.437G>T (p.Arg146Leu) (rs113451409)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172528 SCV000051379 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000172528 SCV000233483 likely benign not provided 2021-03-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 20400443, 23861362, 28600387, 30122538)
Blueprint Genetics RCV000208207 SCV000263849 uncertain significance Cardiac arrest 2015-04-27 criteria provided, single submitter clinical testing
Invitae RCV001080090 SCV000287243 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000243170 SCV000317781 likely benign Cardiovascular phenotype 2020-03-10 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV001080090 SCV000408207 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000172528 SCV000883747 uncertain significance not provided 2017-10-22 criteria provided, single submitter clinical testing The p.Arg146Leu variant was reported in one individual not selected for arrhythmia/cardiomyopathy and classified as a “likely not pathogenic” variant (Ng, 2013). This variant has also been observed in patients with cardiomyopathy, including one from a cohort of surviving cardiac arrest patients (Mellor, 2017), and a single individual with ARCV, who carried a stop codon in the PKP2 gene (Fressart, 2010). In addition, the same codon change to a histidine (p.Arg146His) was reported in one ARCV patient, who was tri-allelic with a frameshift and missense in the PKP2 gene (Rigato, 2013). The p.Arg146Leu variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.04 percent (identified on 110 out of 276,912 chromosomes), and has been reported to the ClinVar database (Variation ID: 44317). The arginine at position 146 is moderately conserved considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Arg146Leu variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Arg146Leu variant with certainty.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770546 SCV000901993 uncertain significance Cardiomyopathy 2017-02-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000770546 SCV000903197 likely benign Cardiomyopathy 2019-10-28 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852471 SCV000995165 uncertain significance Hypertrophic cardiomyopathy 2018-10-30 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172528 SCV001151510 likely benign not provided 2021-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037305 SCV000060962 uncertain significance not specified 2009-09-21 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000037305 SCV000280085 uncertain significance not specified 2013-04-25 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the information reviewed below, we classify it as a variant of unknown significance. This variant has previously been reported in one proband with ARVC who also carried a premature stop codon in PKP2, and the DSG2 variant was categorized as a variant of unknown significance (Fressart et al. 2010). There is no published segregation data. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Leucine. The Arginine at this location is highly conserved across mammalian species, but it is a Proline in birds and the amino acid varies across fish species. This variant is in the cadherin domain. Variation at nearby residues has been associated with ARVC, which may support the functional importance of this region of the protein: Val149Phe, Asp154Glu (HGMD professional version as of January 17, 2014). Kapplinger et al. have proposed a “hot spot” for DSG2 variants between amino acids 24-388 in patients with ARVC but not in controls. This variant does fall within that hot spot. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 0.983. In total the variant has been seen in 9 out of over 60,000 published controls and individuals from publicly available population datasets. This variant is present in 9 Caucasian individuals in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals. Furthermore, a Arg146Cys variant at the same amino acid is present in one African-American individual. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant is present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) as rs113451409, submitted by 6 different sequencing projects or labs. It is not present in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 1/26/2015. The variant was not observed in published controls: 300 Caucasian controls (Fressart et al. 2010). There are 37 individuals in ExAc with this variant and, of these, 1 of them is Latino, 2 are African, 1 is “other”, and 33 are Caucasian.
GenomeConnect, ClinGen RCV000172528 SCV000606918 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000172528 SCV001742076 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000172528 SCV001917473 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000172528 SCV001927121 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000172528 SCV001959399 likely benign not provided no assertion criteria provided clinical testing

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