ClinVar Miner

Submissions for variant NM_001927.4(DES):c.193G>A (p.Gly65Ser)

gnomAD frequency: 0.00007  dbSNP: rs397516692
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037236 SCV000060893 likely benign not specified 2019-12-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Eurofins Ntd Llc (ga) RCV000724220 SCV000224363 uncertain significance not provided 2016-10-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000515205 SCV000611470 uncertain significance Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000724220 SCV000618571 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing The G65S variant has been previously reported as a variant of uncertain significance in an individual with dilated cardiomyopathy; however, segregation analysis and functional studies were not provided (Pugh et al., 2014). The G65S variant is observed in 2/3,696 (0.05%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with DES-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000805979 SCV000945957 uncertain significance Desmin-related myofibrillar myopathy 2023-12-14 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 65 of the DES protein (p.Gly65Ser). This variant is present in population databases (rs397516692, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257, 34011823). ClinVar contains an entry for this variant (Variation ID: 44256). 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 95%. 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.
Illumina Laboratory Services, Illumina RCV001137421 SCV001297355 benign Neurogenic scapuloperoneal syndrome, Kaeser type 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina RCV000805979 SCV001297356 uncertain significance Desmin-related myofibrillar myopathy 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001137423 SCV001297357 uncertain significance Dilated cardiomyopathy 1I 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Revvity Omics, Revvity RCV000724220 SCV003829058 uncertain significance not provided 2020-05-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV004018830 SCV004856352 uncertain significance Cardiovascular phenotype 2021-04-13 criteria provided, single submitter clinical testing The c.193G>A (p.G65S) alteration is located in exon 1 (coding exon 1) of the DES gene. This alteration results from a G to A substitution at nucleotide position 193, causing the glycine (G) at amino acid position 65 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
KTest Genetics, KTest RCV001137423 SCV001499953 likely pathogenic Dilated cardiomyopathy 1I no assertion criteria provided clinical testing

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