ClinVar Miner

Submissions for variant NM_002709.3(PPP1CB):c.548A>T (p.Glu183Val)

dbSNP: rs886037954
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV005252836 SCV005903442 pathogenic RASopathy 2024-12-03 reviewed by expert panel curation The c.548A>T (p.Glu183Val) variant in PPP1CB is a missense variant predicted to cause substitution of glutamate by valine at amino acid 183. This variant is absent from gnomAD v2 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP (PP2). This variant was observed in a proband with a phenotype consistent with RASopathy (PS4_Supporting; PMID:27681385). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:27681385). The variant occurs at the same amino acid residue as the PPP1CB c.548A>C (p.Glu183Ala) variant, which has been classified as pathogenic by the ClinGen RASOpathy VCEP (PM5). Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as likely pathogenic; however, the RASopathy VCEP has upgraded this classification to pathogenic based on ClinGen policy due to the strength of evidence for the PM5 code. In summary, this variant currently meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM5, PP2, PS4_Supporting, PM2_Supporting. (RASopathy VCEP specifications version 1.3; 12/3/2024)
GeneDx RCV000257978 SCV000299376 pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing The E183V variant in the PPP1CB gene has been observed in internal GeneDx whole exome sequencing data in association with developmental delay, congenital heart defect, dysmorphic features, and short stature. The E183V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E183V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E183V as a pathogenic variant.
OMIM RCV000490623 SCV000579312 pathogenic Noonan syndrome-like disorder with loose anagen hair 2 2017-05-31 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.