Submissions for variant NM_000083.3(CLCN1):c.2058C>G (p.Tyr686Ter)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008657	SCV001168436	likely pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing	The Y686X pathogenic variant in the CLCN1 gene has been reported previously in an individual described as having autosomal recessive myotonia congenita, but was seen with a variant that is not classified as pathogenic and segregation information was not provided (Modoni et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies suggested an effect of Y686X on chloride currents, but the methods used in these studies were not clearly described (Desaphy et al., 2013). The Y686X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Y686X as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769412	SCV004587590	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-08-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects CLCN1 function (PMID: 23933576). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 817516). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 21221019). 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 sequence change creates a premature translational stop signal (p.Tyr686*) 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).

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