Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001731461 | SCV000299377 | pathogenic | not provided | 2021-08-08 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27681385, 30236064) |
Ambry Genetics | RCV001266742 | SCV001444919 | pathogenic | Inborn genetic diseases | 2021-03-30 | criteria provided, single submitter | clinical testing | The c.548A>C (p.E183A) alteration is located in exon 5 (coding exon 5) of the PPP1CB gene. This alteration results from an A to C substitution at nucleotide position 548, causing the glutamic acid (E) at amino acid position 183 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the PPP1CB c.548A>C alteration was not observed, with coverage at this position. This alteration has been previously reported in multiple patients with various phenotypes suggestive of Noonan syndrome including global developmental delay, macrocephaly, seizures, congenital heart defects, and dysmorphic features (Ma, 2016; Lin, 2018; Hong 2020). In addition, another alteration affecting the same amino acid, p.E183V, was reported in a patient with a similar neurodevelopmental disorder (Ma, 2016). The p.E183 amino acid is conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The p.E183A alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
Invitae | RCV001731461 | SCV003524181 | pathogenic | not provided | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 183 of the PPP1CB protein (p.Glu183Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 27681385, 30236064). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254652). 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 PPP1CB protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
OMIM | RCV000490621 | SCV000579311 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2017-05-31 | no assertion criteria provided | literature only |