ClinVar Miner

Submissions for variant NM_004393.6(DAG1):c.1954C>T (p.Arg652Trp)

gnomAD frequency: 0.00005  dbSNP: rs151272832
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000292624 SCV000338261 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001859613 SCV002167946 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2P; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9 2022-02-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 652 of the DAG1 protein (p.Arg652Trp). This variant is present in population databases (rs151272832, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DAG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 285302). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Revvity Omics, Revvity RCV000292624 SCV003830410 uncertain significance not provided 2019-04-16 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV003993916 SCV004812445 uncertain significance Qualitative or quantitative defects of alpha-dystroglycan 2023-06-15 criteria provided, single submitter clinical testing This sequence change in DAG1 is predicted to replace arginine with tryptophan at codon 652, p.(Arg652Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in the pepdidase S72 domain. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.008% (10/128,926 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. To our knowledge, this variant has not been reported in the relevant literature in any individuals. Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting.

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