Submissions for variant NM_006907.4(PYCR1):c.355C>T (p.Arg119Cys)

gnomAD frequency: 0.00014  dbSNP: rs121918376

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000578310	SCV001525291	pathogenic	Autosomal recessive cutis laxa type 2B	2019-10-30	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001550766	SCV001771152	pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased protein levels observed in transfected cells, compared to wild type, suggesting the variant is associated with protein instability (Nakayama et al., 2015); This variant is associated with the following publications: (PMID: 30450527, 23963297, 28294978, Tramontana 2021[Case report], 35599849, 24035636, 25865492, 33771508)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001550766	SCV002244565	pathogenic	not provided	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 119 of the PYCR1 protein (p.Arg119Cys). This variant is present in population databases (rs121918376, gnomAD 0.08%). This missense change has been observed in individuals with cutis laxa (PMID: 23963297, 24035636, 30450527). ClinVar contains an entry for this variant (Variation ID: 488456). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PYCR1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PYCR1 function (PMID: 25865492). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509452	SCV002819362	pathogenic	Cutis laxa	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: PYCR1 c.355C>T (p.Arg119Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 246662 control chromosomes. c.355C>T has been reported in the literature in multiple individuals affected with Cutis Laxa - PYCR1 Related phenotypes (Example: Dimopoulou_2013, Gardeitchik_2014, Lessel_2018 and Nakayama_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating less than 2% cell activity compared to Wildtype in lymphoblastoid cell lines (Nakayama_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003992334	SCV004809523	pathogenic	PYCR1-related de Barsy syndrome	2024-04-04	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000578310	SCV000680123	pathogenic	Autosomal recessive cutis laxa type 2B	2017-07-28	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001550766	SCV001800370	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001550766	SCV001808357	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945359	SCV004757029	likely pathogenic	PYCR1-related disorder	2023-12-29	no assertion criteria provided	clinical testing	The PYCR1 c.355C>T variant is predicted to result in the amino acid substitution p.Arg119Cys. This variant was reported in individuals presenting with autosomal recessive cutis laxa (Table 2, Dimopoulou et al. 2013. PubMed ID: 24035636; Table 2, Gardeitchik et al. 2013. PubMed ID: 23963297). It has also been reported in the homozygous state in individuals with microcephaly, hypomyelination, hypotonia, and developmental and white matter anomalies (Nakayama et al. 2015. PubMed ID: 25865492; Individual 6, Lessel et al. 2018. PubMed ID: 30450527). This variant is reported in 0.049% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic.