Submissions for variant NM_000751.3(CHRND):c.727C>T (p.Arg243Cys)

gnomAD frequency: 0.00042  dbSNP: rs201733876

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000285578	SCV000335058	uncertain significance	not provided	2015-09-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000526402	SCV000428415	uncertain significance	Lethal multiple pterygium syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000295199	SCV000428416	uncertain significance	Congenital myasthenic syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526402	SCV000641734	uncertain significance	Lethal multiple pterygium syndrome	2025-02-03	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 243 of the CHRND protein (p.Arg243Cys). This variant is present in population databases (rs201733876, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of CHRND-related conditions (PMID: 32528171). ClinVar contains an entry for this variant (Variation ID: 283138). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CHRND protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000764380	SCV000895432	uncertain significance	Lethal multiple pterygium syndrome; Congenital myasthenic syndrome 3A; Congenital myasthenic syndrome 3B; Congenital myasthenic syndrome 3C	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000285578	SCV001777592	likely benign	not provided	2019-10-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32528171)
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731557	SCV001984037	likely benign	not specified	2020-08-17	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002227466	SCV002507084	uncertain significance	Congenital myasthenic syndrome 3A	2022-05-04	criteria provided, single submitter	curation	The heterozygous p.Arg243Cys variant in CHRND was identified by our study in 1 individual with congenital myasthenic syndrome 3A. The variant has not been previously reported in individuals with congenital myasthenic syndrome 3A but has been identified in 0.06% (14/24950) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201733876). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 283138) as having uncertain significance by multiple submitters. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg243Cys variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015).
Revvity Omics, Revvity	RCV000285578	SCV003833668	likely benign	not provided	2023-10-05	criteria provided, single submitter	clinical testing