ClinVar Miner

Submissions for variant NM_000751.3(CHRND):c.127C>T (p.Arg43Trp) (rs55868108)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485087 SCV000568692 pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing The R43W pathogenic variant in the CHRND gene was previously reported in an individual with congenital myasthenia syndrome who harbored an additional variant on the opposite CHRND allele (Azuma et al., 2015). Functional studies indicate cells harboring the R43W variant result in AChR deficiency at the neuromuscular junction (Azuma et al., 2015). The R43W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000805114 SCV000945058 uncertain significance Lethal multiple pterygium syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 43 of the CHRND protein (p.Arg43Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs55868108, ExAC 0.006%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with congenital myasthenic syndrome (CMS) (PMID: 25264167). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 420109). Experimental studies have shown that this missense change leads to reduced cell-surface expression of acetylcholine receptor (AChR) (PMID: 25264167). 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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