ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5167G>C (p.Glu1723Gln) (rs142803672)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617235 SCV000734916 uncertain significance Cardiovascular phenotype 2017-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172541 SCV000051387 likely benign not provided 2013-06-24 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769230 SCV000900606 uncertain significance Cardiomyopathy 2017-02-02 criteria provided, single submitter clinical testing
GeneDx RCV000038060 SCV000233623 uncertain significance not specified 2016-05-09 criteria provided, single submitter clinical testing The E1723Q variant of uncertain significance in the DSP gene has been previously published as a Class 2, likely notpathogenic" variant, with an allele frequency of 2/1740 (0.1%) among 870 ClinSeq participants who were notpreselected for a personal/family history of cardiac disorders (Ng et al., 2013). Moreover, the NHLBI ExomeSequencing Project and the 1000 Genomes Project report the E1723Q variant was observed in 0.1-0.15% of allelesfrom individuals of European ancestry, indicating it may be a rare benign variant in this population. AlthoughE1723Q has been identified in multiple individuals referred for arrhythmia/cardiomyopathy testing at GeneDx,observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the absolutepathogenicity of this variant. In addition, E1723Q is classified in ClinVar by another clinical laboratory as a variant ofuncertain significance in association with HCM/ARVC (SCV000061726.3; Landrum et al., 2016). The E1723Qvariant occurs at a position that is conserved across species and is a semi-conservative amino acid substitution, whichmay impact secondary protein structure as these residues differ in some properties. However, in silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign."
Invitae RCV000465510 SCV000543285 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1723 of the DSP protein (p.Glu1723Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs142803672, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 44924). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415705 SCV000493739 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-03-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038060 SCV000061726 uncertain significance not specified 2017-01-20 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627160 SCV000748012 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2017-02-06 criteria provided, single submitter clinical testing

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