Submissions for variant NM_001366385.1(CARD14):c.205C>T (p.Arg69Trp)

gnomAD frequency: 0.00022  dbSNP: rs375624435

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000820030	SCV000960722	uncertain significance	Pityriasis rubra pilaris; Psoriasis 2	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 69 of the CARD14 protein (p.Arg69Trp). This variant is present in population databases (rs375624435, gnomAD 0.03%). This missense change has been observed in individual(s) with psoriasis vulgaris or psoriatic arthritis (PMID: 26358359). ClinVar contains an entry for this variant (Variation ID: 662399). 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 CARD14 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CARD14 function (PMID: 26358359). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825881	SCV000967366	uncertain significance	not specified	2018-04-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg69Trp variant in CARD14 has been reported in 5 individuals with psoriasis (Ammar 2016) and has been identified in 0.02% (28/171754) of general population chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs375624435). Computational prediction tools and conservation analysis sugge st that the p.Arg69Trp variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. Functional studies provide s ome evidence that the p.Arg69Trp variant may impact protein function (Ammar 2016 ). However, these types of assays may not accurately represent biological functi on. In summary, while there is some suspicion for a pathogenic role, the clinica l significance of the p.Arg69Trp variant is uncertain. ACMG/AMP Criteria applied : PP3; PS3_Supporting; PS4_Supporting
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002264019	SCV002543258	uncertain significance	Autoinflammatory syndrome	2022-03-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003396441	SCV004112410	likely pathogenic	CARD14-related disorder	2024-01-18	criteria provided, single submitter	clinical testing	The CARD14 c.205C>T variant is predicted to result in the amino acid substitution p.Arg69Trp. This variant has been reported in individuals with classic plaque-type psoriasis vulgaris (PV) and psoriatic arthritis (PA) and experimental studies suggest this variant may impact function (Ammar et al. 2016. PubMed ID: 26358359). Additionally, an alternate missense variant (p.Arg69Gln) has been reported in pustular psoriasis (Körber et al. 2013. PubMed ID: 23648549). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.