Submissions for variant NM_000492.4(CFTR):c.127G>A (p.Val43Ile)

gnomAD frequency: 0.00002  dbSNP: rs370586917

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002488	SCV001160439	uncertain significance	not specified	2019-04-06	criteria provided, single submitter	clinical testing	The CFTR c.127G>A; p.Val43Ile variant (rs370586917), to our knowledge, is not described in the medical literature or in gene-specific databases. It is observed in the general population at an overall frequency of 0.0032% (9/282264 alleles) in the Genome Aggregation Database. The valine at codon 43 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.
Illumina Laboratory Services, Illumina	RCV001161751	SCV001323652	uncertain significance	CFTR-related disorders	2018-01-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001002488	SCV001370729	uncertain significance	not specified	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.127G>A (p.Val43Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250868 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.127G>A in individuals affected with Cystic Fibrosis/Chronic Pancreatitis Risk/CFTR-related disorders 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.
Invitae	RCV001246599	SCV001419964	uncertain significance	Cystic fibrosis	2022-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 43 of the CFTR protein (p.Val43Ile). This variant is present in population databases (rs370586917, gnomAD 0.008%). 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: 811961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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-Nilou Lab	RCV001246599	SCV002027330	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001246599	SCV002689032	uncertain significance	Cystic fibrosis	2022-06-16	criteria provided, single submitter	clinical testing	The p.V43I variant (also known as c.127G>A), located in coding exon 2 of the CFTR gene, results from a G to A substitution at nucleotide position 127. The valine at codon 43 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available 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	RCV002497321	SCV002806178	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-12-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478604	SCV004221656	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000062 (8/128700 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV003478604	SCV004224068	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	BP4, PM2
Natera, Inc.	RCV001246599	SCV001453942	uncertain significance	Cystic fibrosis	2018-05-23	no assertion criteria provided	clinical testing