ClinVar Miner

Submissions for variant NM_031229.4(RBCK1):c.1336C>T (p.Arg446Cys)

gnomAD frequency: 0.00014  dbSNP: rs372540581
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768067 SCV000898929 uncertain significance Polyglucosan body myopathy type 1 2021-03-30 criteria provided, single submitter clinical testing RBCK1 NM_031229.3 exon 11 p.Arg446Cys (c.1336C>T): This variant has not been reported in the literature but is present in 0.008% (2/24500) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-409622-C-T). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000768067 SCV000930941 uncertain significance Polyglucosan body myopathy type 1 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 446 of the RBCK1 protein (p.Arg446Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RBCK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 626004). 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 RBCK1 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.

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