ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3650C>T (p.Ala1217Val) (rs749662161)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999841 SCV000603015 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing The CFTR c.3650C>T, p.Ala1217Val variant (rs749662161) has not been reported in the medical literature but is reported in ClinVar (Variation ID: 439480). It is observed on five chromosomes in the Genome Aggregation Database general population database (5/244922 alleles). The alanine at residue 1217 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ala1217Val variant is uncertain at this time.
Integrated Genetics/Laboratory Corporation of America RCV000587924 SCV000696978 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3650C>T (p.Ala1217Val) variant located in the AAA+ ATPase domain (via InterPro) involves the alteration of a conserved nucleotide that 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120906 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000797225 SCV000936774 uncertain significance Cystic fibrosis 2018-12-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1217 of the CFTR protein (p.Ala1217Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs749662161, ExAC 0.01%). This variant has not been reported in the literature in individuals with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 439480). 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, suggesting that this missense change does not adversely affect protein function. 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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