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

gnomAD frequency: 0.00001  dbSNP: rs794728104

Total submissions: 7

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, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641787	SCV000763436	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1927 of the DSP protein (p.Gln1927Glu). This variant is present in population databases (rs794728104, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001189661	SCV001356992	uncertain significance	Cardiomyopathy	2022-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 1927 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250848 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.
Ambry Genetics	RCV003165383	SCV003867623	uncertain significance	Cardiovascular phenotype	2023-02-28	criteria provided, single submitter	clinical testing	The p.Q1927E variant (also known as c.5779C>G), located in coding exon 24 of the DSP gene, results from a C to G substitution at nucleotide position 5779. The glutamine at codon 1927 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181264	SCV003929367	uncertain significance	not specified	2023-04-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996635	SCV004823475	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 1927 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250848 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.