Submissions for variant NM_005198.5(CHKB):c.722A>G (p.Asn241Ser)

gnomAD frequency: 0.00002  dbSNP: rs371751084

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000329772	SCV000439360	uncertain significance	Megaconial type congenital muscular dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	The CHKB c.722A>G (p.Asn241Ser) variant has been reported in two studies in two individuals with congenital muscular dystrophy, one in a homozygous state and the other in a compound heterozygous state with another missense variant (Quinlivan et al. 2013; Mitsuhashi et al. 2013). Mitsuhashi et al. (2013) demonstrated that recombinant CHKB protein created with the p.Asn241Ser variant showed marked decrease in choline kinase activities. The p.Asn241Ser variant is reported at a frequency of 0.0002269 in the African American population of the Exome Sequencing Project, but this is based on one allele only in a region of good sequence converage and is presumed to be rare. Based on the evidence, the p.Asn241Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for CHKB-related congenital muscular dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000329772	SCV005842197	likely pathogenic	Megaconial type congenital muscular dystrophy	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 241 of the CHKB protein (p.Asn241Ser). This variant is present in population databases (rs371751084, gnomAD 0.007%). This missense change has been observed in individuals with congenital muscular dystrophy (PMID: 23692895, 26548592). ClinVar contains an entry for this variant (Variation ID: 342172). 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 CHKB protein function with a positive predictive value of 80%. 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.