ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2831dup (p.Gly945fs) (rs755176513)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000307053 SCV000612786 pathogenic not provided 2017-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000307053 SCV000329933 likely pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing The c.2831dupC likely pathogenic variant in the CLCN1 gene has been reported previously as c.2828insC due to alternative nomenclature, in an individual with severe myotonia, tongue myotonia, and lid myotonia, who also harbored a second CLCN1 pathogenic variant, suggestive of autosomal recessive inheritance (Dupree et al., 2009). The duplication causes a frameshift starting with codon Glycine 945, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 39 of the new reading frame, denoted p.Gly945ArgfsX39. This likely pathogenic variant is predicted to cause loss of normal protein function through protein truncation as the last 44 amino acid residues are replaced with 38 incorrect amino acid residues. The c.2831dupC variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000705425 SCV000834421 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-09-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CLCN1 gene (p.Gly945Argfs*39). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acids of the CLCN1 protein. This variant is present in population databases (rs755176513, ExAC 0.003%). This variant has been observed to be homozygous or in combination with another CLCN1 variant in individuals affected with myotonia congenita (PMID: 18337100, Invitae). This variant is also known as c.2828insC in the literature. ClinVar contains an entry for this variant (Variation ID: 280103). For these reasons, this variant has been classified as Pathogenic.

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