ClinVar Miner

Submissions for variant NM_031229.4(RBCK1):c.1054C>T (p.Arg352Ter)

gnomAD frequency: 0.00001  dbSNP: rs780854072
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000703630 SCV000832539 pathogenic Polyglucosan body myopathy type 1 2023-07-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg352*) in the RBCK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RBCK1 are known to be pathogenic (PMID: 2379848, 23104095, 23889995). This variant is present in population databases (rs780854072, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with polyglucosan body myopathy and dilated cardiomyopathy (PMID: 23798481). ClinVar contains an entry for this variant (Variation ID: 580166). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center RCV000703630 SCV004037375 pathogenic Polyglucosan body myopathy type 1 2019-06-14 criteria provided, single submitter clinical testing The c.1054C>T, p.Arg352* variant in the RBCK1 gene is a homozygous nonsense variant which results in premature truncation of the protein at exon 9/12. The allele frequency of this variant in the gnomAD database is 0.00001194 (3/251,356) without homozygotes, suggesting that it is not a common benign polymorphism in the populations presented in this database. This variant in the homozygous state has been previously reported as disease causing in one family (PMID: 23798481). Pathogenic variants in the RBCK1 gene are causative of autosomal recessive polyglucosan body myopathy 1 with or without immunodeficiency (OMIM#: 615895). Several truncating RBCK1 variants have been reported in multiple patients/families with the disease, suggesting the disease mechanism is loss of function (PMID: 23798481).

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