Submissions for variant NM_000492.4(CFTR):c.697C>G (p.Leu233Val)

gnomAD frequency: 0.00003  dbSNP: rs775713428

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000435093	SCV000531739	uncertain significance	not provided	2016-09-21	criteria provided, single submitter	clinical testing	The L233V variant in the CFTR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L233V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L233V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (V232D, Q237E, Q237H) have been reported in the Human Gene Mutation Database in association with cystic fibrosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L233V as a variant of uncertain significance.
Johns Hopkins Genomics, Johns Hopkins University	RCV001007618	SCV001167309	uncertain significance	Cystic fibrosis	2019-11-25	criteria provided, single submitter	clinical testing	This CFTR variant has not been reported in the literature in patients with cystic fibrosis to our knowledge. It is classified as a variant of uncertain clinical significance in ClinVar by a single submitter. This variant (rs775713428) is rare (<0.1%) in a large population dataset (gnomAD: 8/251378 total alleles; 0.0032%; no homozygotes). Three bioinformatic tools queried predict that this substitution would be tolerated. The leucine residue at this position is not highly evolutionarily conserved across the species assessed and a valine is present at this position in multiple species. We consider the clinical significance of c.697C>G to be uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584120	SCV001821252	uncertain significance	not specified	2021-08-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.697C>G (p.Leu233Val) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251378 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.697C>G in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001007618	SCV002027366	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000435093	SCV002540890	uncertain significance	not provided	2021-05-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001007618	SCV002665133	uncertain significance	Cystic fibrosis	2020-03-01	criteria provided, single submitter	clinical testing	The p.L233V variant (also known as c.697C>G), located in coding exon 6 of the CFTR gene, results from a C to G substitution at nucleotide position 697. The leucine at codon 233 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. 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.
Fulgent Genetics, Fulgent Genetics	RCV002481326	SCV002780555	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-01-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001007618	SCV003468774	uncertain significance	Cystic fibrosis	2022-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 233 of the CFTR protein (p.Leu233Val). This variant is present in population databases (rs775713428, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 389270). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000435093	SCV005878478	uncertain significance	not provided	2024-08-06	criteria provided, single submitter	clinical testing	The CFTR c.697C>G; p.Leu233Val variant (rs775713428), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 389270). This variant is observed in the general population with an overall allele frequency of 0.003% (8/251378 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.28). Due to limited information, the clinical significance of this variant is uncertain at this time.
Natera, Inc.	RCV001007618	SCV001453953	uncertain significance	Cystic fibrosis	2018-07-03	no assertion criteria provided	clinical testing