Submissions for variant NM_000079.4(CHRNA1):c.1321G>A (p.Gly441Arg)

gnomAD frequency: 0.00004  dbSNP: rs768407867

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522179	SCV000618396	pathogenic	not provided	2024-02-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced expression as compared to wild-type protein (PMID: 24121633); 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: 27748205, 24121633, 34749429, 36007526, 37432431)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542688	SCV000641698	pathogenic	Lethal multiple pterygium syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 441 of the CHRNA1 protein (p.Gly441Arg). This variant is present in population databases (rs768407867, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive severe congenital myasthenic syndrome (PMID: 24121633, 27748205; Invitae). 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 p.Gly421Arg and p.Gly466Arg. ClinVar contains an entry for this variant (Variation ID: 449923). 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 CHRNA1 protein function. Experimental studies have shown that this missense change affects CHRNA1 function (PMID: 24121633). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000522179	SCV002817255	likely pathogenic	not provided	2021-10-08	criteria provided, single submitter	clinical testing	This variant appears to segregate with disease in at least one family (PMID: 27748205). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 24121633). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Revvity Omics, Revvity	RCV000522179	SCV003818608	likely pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586756	SCV005038545	pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PS3+PM1+PM2+PP2+PP3+PP4+PP5
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000679850	SCV000807193	pathogenic	Autism; Seizure	2017-03-24	no assertion criteria provided	clinical testing