Submissions for variant NM_005199.5(CHRNG):c.715C>T (p.Arg239Cys)

gnomAD frequency: 0.00001  dbSNP: rs121912670

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000020003	SCV001976949	pathogenic	Autosomal recessive multiple pterygium syndrome	2021-10-01	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PP3, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020004	SCV003844793	pathogenic	Lethal multiple pterygium syndrome	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: CHRNG c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence, altering a highly conserved residue (HGMD, Hoffmann_2006). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251486 control chromosomes. c.715C>T has been reported in the literature in multiple individuals affected with Escobar syndrome and arthrogryposis with evidence of cosegregation (Bayram_2016, Hoffmann_2006, Laquerriere_2014, Marinakis_2021), and at least one patient was reported as compound heterozygous with another likely pathogenic variant. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding no AChR expression at the cellular surface when transfecting HEK cells with a construct carrying the variant (Hoffmann_2006). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV003556054	SCV004279244	pathogenic	not provided	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the CHRNG protein (p.Arg239Cys). This variant is present in population databases (rs121912670, gnomAD 0.003%). This missense change has been observed in individuals with CHRNG-related conditions (PMID: 16826520, 24319099, 26752647, 29054425, 30868735). This variant is also known as p.Arg217Cys. ClinVar contains an entry for this variant (Variation ID: 18337). 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 CHRNG protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CHRNG function (PMID: 16826520). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000020003	SCV000040301	pathogenic	Autosomal recessive multiple pterygium syndrome	2006-08-01	no assertion criteria provided	literature only
OMIM	RCV000020004	SCV000040302	pathogenic	Lethal multiple pterygium syndrome	2006-08-01	no assertion criteria provided	literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000020003	SCV001167524	likely pathogenic	Autosomal recessive multiple pterygium syndrome		no assertion criteria provided	research