Submissions for variant NM_001104631.2(PDE4D):c.674C>T (p.Pro225Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002640726	SCV003525722	pathogenic	not provided	2024-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the PDE4D protein (p.Pro225Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acrodysostosis (PMID: 23033274). In at least one individual the variant was observed to be de novo. This variant is also known as c.491C>T (p.Pro164Leu). ClinVar contains an entry for this variant (Variation ID: 2203651). 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 expected to disrupt PDE4D protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PDE4D function (PMID: 24203977). This variant disrupts the p.Pro225 amino acid residue in PDE4D. Other variant(s) that disrupt this residue have been observed in individuals with PDE4D-related conditions (PMID: 22464250, 26633542), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002640726	SCV005324990	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24203977, 26763073, 23033274)
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV004790402	SCV005413150	pathogenic	Acrodysostosis 2 with or without hormone resistance	2024-03-26	criteria provided, single submitter	clinical testing