Submissions for variant NM_000083.3(CLCN1):c.1261dup (p.Arg421fs)

dbSNP: rs763633152

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000516577	SCV000612757	pathogenic	not provided	2023-05-05	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 29606556, 8533761).
Invitae	RCV000691433	SCV000819211	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg421Profs*9) in the CLCN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs763633152, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 8533761). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 1262insC. ClinVar contains an entry for this variant (Variation ID: 447048). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193451	SCV001362283	pathogenic	Congenital myotonia, autosomal recessive form	2019-05-24	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1261dupC (p.Arg421ProfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251658 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Congenital and generalized myotonia in an autosomal recessive form (Meyer-Kleine_1995, Stunnenberg_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000516577	SCV002017370	pathogenic	not provided	2020-11-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000516577	SCV002097433	pathogenic	not provided	2022-08-11	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8533761, 31589614, 35170402, 35350395)
Fulgent Genetics, Fulgent Genetics	RCV000691433	SCV002799217	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-01-28	criteria provided, single submitter	clinical testing