ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5779C>G (p.Gln1927Glu) (rs794728104)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766885 SCV000233549 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The Q1927E variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been classifiedin ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000271735.1; Landrum etal., 2016). In addition, the Q1927E variant has previously been identified in one other unrelated individual referred forcardiomyopathy genetic testing at GeneDx who also harbored a pathogenic variant in the RAF1 gene. This variantwas not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The Q1927E variantis a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differin some properties. This substitution occurs at a position that is conserved in mammals. However, Glutamic acid isthe wild type amino acid at this position in multiple species. Furthermore, in silico analysis is inconsistent in itspredictions 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000181264 SCV000271735 uncertain significance not specified 2015-04-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gln1927Glu va riant in DSP has not been previously reported in individuals with cardiomyopathy or in large population studies. Glutamine (Gln) at position 1927 is conserved i n mammals but not in evolutionarily distant species and >10 avian species carry a glutamic acid (Glu), raising the possibility that this change may be tolerated . Additional computational prediction tools support that the p.Gln1927Glu varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. In summary, while the clinical significance of the p.G ln1927Glu variant is uncertain, the presence of the variant amino acid in multip le other species suggests that it is more likely to be benign.
Invitae RCV000641787 SCV000763436 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-10-09 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 1927 of the DSP protein (p.Gln1927Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199844). 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 and their clinical significance is uncertain. 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.

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