ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs55868108
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485087 SCV000568692 pathogenic not provided 2021-09-22 criteria provided, single submitter clinical testing Published functional studies indicate cells harboring the R43W variant result in AChR deficiency at the neuromuscular junction (Azuma et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22678886, 25264167)
Invitae RCV000805114 SCV000945058 likely pathogenic Lethal multiple pterygium syndrome 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 43 of the CHRND protein (p.Arg43Trp). This variant is present in population databases (rs55868108, gnomAD 0.009%). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 25264167). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 420109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRND protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CHRND function (PMID: 25264167). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV001332575 SCV001524945 uncertain significance Congenital myasthenic syndrome 3A 2019-07-14 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity RCV000485087 SCV002019297 pathogenic not provided 2019-07-10 criteria provided, single submitter clinical testing

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