ClinVar Miner

Submissions for variant NM_001039523.3(CHRNA1):c.1396G>A (p.Gly466Arg) (rs768407867)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522179 SCV000618396 likely pathogenic not provided 2017-04-24 criteria provided, single submitter clinical testing The G441R variant in the CHRNA1 gene has been reported previously, in the homozygous state, in a male with severe congenital myopathy, bilateral ptosis, complete ophthalmoplegia, absence of facial expression, high-arched palate, hypotonia without contractures, normal creatine kinase level, and a muscle biopsy showing marked predominance and atrophy of type 2 fibers. Treatment of this individual with pyridostigmine reportedly had an almost immediate improvement in limb movement, being able to raise his arms and legs against gravity, and gradual improvement in ventilatory function and reduced BiPAP support (Abath Neto et al., 2017). The G441R variant is observed in 5/11562 (0.04%) alleles from individuals of Latino background, in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The G441R 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G441R as a likely pathogenic variant.
Invitae RCV000542688 SCV000641698 pathogenic Lethal multiple pterygium syndrome 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 441 of the CHRNA1 protein (p.Gly441Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs768407867, ExAC 0.04%). This variant has been reported in two individuals affected with severe congenital myasthenic syndrome (PMID: 24121633, 27748205). In one of these individuals it was observed on the opposite chromosome (in trans) from a different likely pathogenic CHRNA1 variant, and a family study found co-segregation with disease that was consistent with autosomal recessive inheritance (PMID: 24121633). This variant has also been observed in trans with a pathogenic variant in an individual affected with congenital myasthenic syndrome (Invitae). This variant is also known as p.Gly421Arg and p.Gly466Arg in the literature. Experimental studies in transfected cells have shown that this missense change reduces the expression levels of CHRNA1 protein (PMID: 24121633). For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000679850 SCV000807193 pathogenic Seizures; Autism 2017-03-24 no assertion criteria provided clinical testing

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