ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.127G>A (p.Val43Ile) (rs370586917)

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Total submissions: 4
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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 Clinical Services Laboratory,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.
Integrated Genetics/Laboratory Corporation of America RCV001002488 SCV001370729 uncertain significance not specified 2020-05-21 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 (gnomAD). 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 Chronic Pancreatitis Risk and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites 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 2019-08-21 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 43 of the CFTR protein (p.Val43Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs370586917, ExAC 0.01%). This variant has not been reported in the literature in individuals with CFTR-related conditions. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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