Submissions for variant NM_001927.4(DES):c.1286G>A (p.Arg429Gln)

dbSNP: rs200580581

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000357490	SCV000344431	uncertain significance	not provided	2017-09-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617457	SCV000737286	uncertain significance	Cardiovascular phenotype	2022-10-18	criteria provided, single submitter	clinical testing	The p.R429Q variant (also known as c.1286G>A), located in coding exon 7 of the DES gene, results from a G to A substitution at nucleotide position 1286. The arginine at codon 429 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in hypertrophic cardiomyopathy cohorts and co-occurred with variants in other cardiac-related genes; however, clinical details were limited in some cases (Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Thomson KL et al. Genet Med, 2019 07;21:1576-1584; Limongelli G et al. Genes (Basel), 2020 05;11:[ePub ahead of print]). 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.
Invitae	RCV000694336	SCV000822776	uncertain significance	Desmin-related myofibrillar myopathy	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 429 of the DES protein (p.Arg429Gln). This variant is present in population databases (rs200580581, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal dominant DES-related conditions (PMID: 23396983, 32397162). ClinVar contains an entry for this variant (Variation ID: 289962). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
GeneDx	RCV000357490	SCV001826225	uncertain significance	not provided	2022-05-24	criteria provided, single submitter	clinical testing	Reported previously as a likely pathogenic, maternally inherited heterozygous variant in a patient with suspected ARVC; however, the patient also had compound heterozygous variants in another gene and it was thought that all three variants caused a more severe phenotype. The mother was reported to be unaffected (Limongelli et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 23396983, 26807690, 32397162)
Fulgent Genetics, Fulgent Genetics	RCV002487276	SCV002787856	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2021-07-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000357490	SCV003829018	uncertain significance	not provided	2019-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226276	SCV003922857	uncertain significance	not specified	2023-03-01	criteria provided, single submitter	clinical testing	Variant summary: DES c.1286G>A (p.Arg429Gln) results in a conservative amino acid change in the encoded protein sequence, altering a highly conserved residue (HGMD). Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251480 control chromosomes. The observed variant frequency is slightly greater than estimated maximal expected allele frequency for a pathogenic variant in DES causing Dilated Cardiomyopathy phenotype (3.1e-05), suggesting that the variant is benign polymorphism. c.1286G>A has been reported in the literature in individuals affected with Cardiomyopathy without evidence of cosegregation (Lopes_2013, Thomson_2019, Limongelli_2020, Sepp_2022). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrences with other pathogenic variants have been reported among these individuals (MYH7 c.2389G>A, p.Ala797Thr; PKP2 c.368G>A, p.Trp123Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.