Submissions for variant NM_001366385.1(CARD14):c.1199G>A (p.Arg400His)

gnomAD frequency: 0.00016  dbSNP: rs147466598

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802082	SCV000941896	uncertain significance	Pityriasis rubra pilaris; Psoriasis 2	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 400 of the CARD14 protein (p.Arg400His). This variant is present in population databases (rs147466598, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CARD14-related conditions. ClinVar contains an entry for this variant (Variation ID: 647550). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263992	SCV002543214	uncertain significance	Autoinflammatory syndrome	2019-03-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354378	SCV001548984	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CARD14 p.Arg400His variant was not identified in the literature but was identified in dbSNP (ID: rs147466598) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 34 of 281508 chromosomes at a frequency of 0.000121 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 7208 chromosomes (freq: 0.000278), European (non-Finnish) in 31 of 127960 chromosomes (freq: 0.000242) and African in 1 of 24916 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Arg400 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.