Submissions for variant NM_020549.5(CHAT):c.1679G>A (p.Arg560His)

gnomAD frequency: 0.00001  dbSNP: rs121912819

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000019062	SCV001231146	likely pathogenic	Familial infantile myasthenia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 560 of the CHAT protein (p.Arg560His). This variant is present in population databases (rs121912819, gnomAD 0.1%). This missense change has been observed in individuals with clinical features of congenital myasthenic syndrome (PMID: 11172068; Invitae). This variant is also known as R442H. ClinVar contains an entry for this variant (Variation ID: 17510). 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 CHAT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CHAT function (PMID: 11172068, 15381704). 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.
3billion	RCV000019062	SCV002058843	uncertain significance	Familial infantile myasthenia	2022-01-03	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000088, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, 3CNET: 0.778, PP3_P). A missense variant is a common mechanism associated with Myasthenic syndrome (PP2_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271372	SCV002555851	uncertain significance	not specified	2022-06-13	criteria provided, single submitter	clinical testing	Variant summary: CHAT c.1679G>A (p.Arg560His) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain of the encoded protein sequence. 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 8.8e-05 in 251294 control chromosomes, predominantly at a frequency of 0.0013 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome phenotype (0.00079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1679G>A has been reported in the literature in one individual affected with Congenital Myasthenic Syndrome (Ohno_2001). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Ohno_2001, Dobransky_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV001579920	SCV003761570	likely pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Previously reported in an individual with CMS who had a second CHAT variant, however segregation data was not provided (Ohno et al., 2001); Published functional studies demonstrate that this variant results in lack of catalytic efficiency of the ChAT enzyme (Ohno et al., 2001; Albers et al., 2014); 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: 31589614, 26080897, 11172068, 19688192, 24844149, 15131697, 33650116, 15381704, 15477102, 29783273)
Baylor Genetics	RCV000019062	SCV004215795	likely pathogenic	Familial infantile myasthenia	2024-03-07	criteria provided, single submitter	clinical testing
OMIM	RCV000019062	SCV000039349	pathogenic	Familial infantile myasthenia	2001-02-13	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579920	SCV001809034	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579920	SCV001959172	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001579920	SCV001963259	uncertain significance	not provided		no assertion criteria provided	clinical testing