Submissions for variant NM_001927.4(DES):c.154C>A (p.Arg52Ser)

dbSNP: rs794728990

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766841	SCV000235796	uncertain significance	not provided	2014-09-15	criteria provided, single submitter	clinical testing	p.Arg52Ser (CGC>AGC): c.154 C>A in exon 1 of the DES gene (NM_001927.3)The R52S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R52S variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these population. The R52S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in a nearby residue (S46F, S46Y) have been reported in association with desmin-related myopathy, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV000233855	SCV000287219	uncertain significance	Desmin-related myofibrillar myopathy	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 52 of the DES protein (p.Arg52Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 201712). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DES protein function with a negative predictive value of 80%. 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	RCV000251066	SCV000318673	uncertain significance	Cardiovascular phenotype	2022-07-05	criteria provided, single submitter	clinical testing	The p.R52S variant (also known as c.154C>A), located in coding exon 1 of the DES gene, results from a C to A substitution at nucleotide position 154. The arginine at codon 52 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	RCV000183359	SCV001338381	uncertain significance	not specified	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: DES c.154C>A (p.Arg52Ser) results in a non-conservative amino acid change located in the Intermediate filament head, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 223204 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.154C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183359	SCV000280070	uncertain significance	not specified	2013-09-30	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. Given novelty, (reviewed below) we also consider this variant to be of uncertain significance. This variant is novel. To the best of our knowledge, it has not been described in association with disease or in healthy control individuals to date. This particular variant is a semi-conservative amino acid substitution, where a positively charged polar arginine residue is exchanged for an uncharged polar serine residue. The arginine at this position is conserved across species. In silico analysis is inconsistent in its predictions of pathogenicity (while Mutation Taster predicts disease causing, PolyPhen predicts benign). Other variants have been reported in association with desmin-related myopathy at nearby codons (Ser46Phe, Ser46Tyr). In total, the variant has not been seen in approximately 6,000 individuals from publicly available population datasets. There is no variation at codon 52 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of Decembr 7, 2014). There is also no variation at this codon listed in dbSNP or 1000 genomes; and no variation at this codon listed in the ExAC database (thus it is absent from ~65,000 individuals of varying ancestries from the general population as of Dec 7 2014).