Submissions for variant NM_002709.3(PPP1CB):c.658C>T (p.Arg220Cys)

dbSNP: rs1553311527

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523298	SCV000618322	likely pathogenic	not provided	2017-03-17	criteria provided, single submitter	clinical testing	The R220C variant in the PPP1CB gene has not been reported previously as a pathogenic variant, noras a benign variant, to our knowledge. The R220C variant is not observed in large population cohorts(Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R220C variantis a non-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species and in silico analysis predicts this variant is probablydamaging to the protein structure/function. The R220C variant is a strong candidate for a pathogenicvariant; however the possibility it may be a rare benign variant cannot be excluded.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470896	SCV002766949	pathogenic	Noonan syndrome-like disorder with loose anagen hair 2	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome-like disorder with loose anagen hair 2 (MIM#617506) (PMID: 30348783). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in an unrelated individual. This variant has been described as likely pathogenic, and observed as de novo in an individual with developmental delay, intellectual disability, hypotonia, and a history of congenital heart disease (ClinVar, GeneDx personal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign