Submissions for variant NM_001927.4(DES):c.79G>A (p.Gly27Ser)

gnomAD frequency: 0.00001  dbSNP: rs727504877

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156244	SCV000205960	uncertain significance	not specified	2013-12-11	criteria provided, single submitter	clinical testing	The Gly27Ser variant in DES has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to assess th e frequency of this variant. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong supp ort for or against an impact to the protein. Additional information is needed t o fully assess the clinical significance of the Glu838Gln variant.
GeneDx	RCV000766816	SCV000571285	uncertain significance	not provided	2016-08-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DES gene. While the G27S variant has not been published as a pathogenic or a benign variant to our knowledge, it has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000205960.3; Landrum et al., 2016). The G27S variant was not observed in approximately 5,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 8.0). The G27S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is conserved only in mammals. Finally, in silico analysis is inconsistent 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 rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700537	SCV000829296	uncertain significance	Desmin-related myofibrillar myopathy	2022-05-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the DES protein (p.Gly27Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with myopathy (PMID: 22215463). ClinVar contains an entry for this variant (Variation ID: 179455). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV002415673	SCV002678620	uncertain significance	Cardiovascular phenotype	2023-09-27	criteria provided, single submitter	clinical testing	The p.G27S variant (also known as c.79G>A), located in coding exon 1 of the DES gene, results from a G to A substitution at nucleotide position 79. The glycine at codon 27 is replaced by serine, an amino acid with similar properties. This variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases. (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766816	SCV001740408	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766816	SCV001917181	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766816	SCV001930226	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766816	SCV001956256	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766816	SCV001966353	uncertain significance	not provided		no assertion criteria provided	clinical testing