Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV001775100 | SCV002011923 | pathogenic | Lethal multiple pterygium syndrome | 2021-10-02 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (ClinVar ID: VCV000217751.1, PMID: 25608830, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00000795, PM2). The variant was observed in trans with a pathogenic variant (NM_005199.4: c.240+1del, NM_005199.5:c.753_754del) as compound heterozygous (PMID: 25608830, 3billion dataset, PM3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95, 3Cnet: 0.745, PP3). Patient's phenotype is considered compatible with Escobar syndrome (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001775100 | SCV002766283 | pathogenic | Lethal multiple pterygium syndrome | 2022-11-17 | criteria provided, single submitter | clinical testing | Variant summary: CHRNG c.428C>G (p.Pro143Arg) results in a non-conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) 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 8e-06 in 251468 control chromosomes (gnomAD). c.428C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Non-Lethal Multiple Pterygium Syndrome (Escobar Syndrome, Sung_2015, Seo_2015, Seo_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV003556250 | SCV004292169 | pathogenic | not provided | 2023-08-14 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt CHRNG protein function. ClinVar contains an entry for this variant (Variation ID: 217751). This missense change has been observed in individual(s) with clinical features of multiple pterygium syndrome (PMID: 25608830, 32901917). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs765746795, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 143 of the CHRNG protein (p.Pro143Arg). |
| OMIM | RCV000201797 | SCV000256539 | pathogenic | Autosomal recessive multiple pterygium syndrome | 2015-04-01 | no assertion criteria provided | literature only |