Submissions for variant NM_006907.4(PYCR1):c.722C>A (p.Ala241Asp)

dbSNP: rs770505872

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002031595	SCV002311372	uncertain significance	not provided	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 241 of the PYCR1 protein (p.Ala241Asp). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ala241 amino acid residue in PYCR1. Other variant(s) that disrupt this residue have been observed in individuals with PYCR1-related conditions (PMID: 23531708, 24035636), which suggests that this may be a clinically significant amino acid residue. 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 PYCR1 protein function. ClinVar contains an entry for this variant (Variation ID: 1524275). This missense change has been observed in individual(s) with De Barsy syndrome and cutis laxa (PMID: 24035636).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782865	SCV005394139	likely pathogenic	Cutis laxa	2024-09-27	criteria provided, single submitter	clinical testing	Variant summary: PYCR1 c.722C>A (p.Ala241Asp) results in a non-conservative amino acid change located in the Pyrroline-5-carboxylate reductase, dimerisation domain (IPR029036) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246914 control chromosomes. c.722C>A has been reported in the literature in homozygous individuals affected with Cutis Laxa - PYCR1 Related (Dimopoulou_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24035636). ClinVar contains an entry for this variant (Variation ID: 1524275). Based on the evidence outlined above, the variant was classified as likely pathogenic.