ClinVar Miner

Submissions for variant NM_001927.4(DES):c.662C>T (p.Ala221Val)

gnomAD frequency: 0.00004  dbSNP: rs746814065
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000801036 SCV000940788 uncertain significance Desmin-related myofibrillar myopathy 2024-01-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 221 of the DES protein (p.Ala221Val). This variant is present in population databases (rs746814065, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 32528171). ClinVar contains an entry for this variant (Variation ID: 646696). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. 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 RCV002360950 SCV002663189 uncertain significance Cardiovascular phenotype 2023-05-30 criteria provided, single submitter clinical testing The p.A221V variant (also known as c.662C>T), located in coding exon 3 of the DES gene, results from a C to T substitution at nucleotide position 662. The alanine at codon 221 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a cohort of subjects with limb girdle weakness (Töpf A et al. Genet Med, 2020 Sep;22:1478-1488). 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.
Fulgent Genetics, Fulgent Genetics RCV002495071 SCV002780068 uncertain significance Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type 2021-09-30 criteria provided, single submitter clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV003447565 SCV004175180 uncertain significance Hypertrophic cardiomyopathy 2023-11-24 criteria provided, single submitter clinical testing Heterozygous variant NM_001927:c.662C>T (p.Ala221Val) in the DES gene was found on WES data in male proband (44 y.o., Caucasian) with hypertrophic cardiomyopathy. Additional rare candidate variants NM_001276345:c.862C>T (Class III of pathogenicity) in the TNNT2 gene and NM_003476:c.357G>T (Class III of pathogenicity) in the CSRP3 gene were found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 and v4.0.0 with total MAF 0.00004242 and 0.00002044 respectively (Date of access 24-01-2023). Clinvar contains an entry for this variant (Variation ID: 646696). This variant has been reported in 1 study in patient with limb-girdle weakness. Most in silico predictors are inconclusive in the results (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2.

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