Submissions for variant NM_017950.4(CCDC40):c.1150C>T (p.Arg384Cys)

gnomAD frequency: 0.00001  dbSNP: rs758068198

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001122108	SCV001280802	uncertain significance	Primary ciliary dyskinesia 15	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001299590	SCV001488687	uncertain significance	Primary ciliary dyskinesia	2020-02-12	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CCDC40-related disease. This variant is present in population databases (rs758068198, ExAC 0.3%). This sequence change replaces arginine with cysteine at codon 384 of the CCDC40 protein (p.Arg384Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
Ambry Genetics	RCV001299590	SCV002623969	uncertain significance	Primary ciliary dyskinesia	2022-01-05	criteria provided, single submitter	clinical testing	The p.R384C variant (also known as c.1150C>T), located in coding exon 7 of the CCDC40 gene, results from a C to T substitution at nucleotide position 1150. The arginine at codon 384 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.