ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.490A>G (p.Thr164Ala) (rs200885306)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780137 SCV000917182 uncertain significance not specified 2018-12-13 criteria provided, single submitter clinical testing Variant summary: CFTR c.490A>G (p.Thr164Ala) results in a non-conservative amino acid change of the first nucleotide of exon 5, located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 275348 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.490A>G in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000802964 SCV000942815 uncertain significance Cystic fibrosis 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 164 of the CFTR protein (p.Thr164Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs200885306, ExAC 0.005%). This variant has not been reported in the literature in individuals with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 632754). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000780137 SCV001160242 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing The CFTR c.490A>G; p.Thr164Ala variant (rs200885306), to our knowledge, is not reported in the medical literature but is reported in the Sick Kids CFTR database (see link). This variant is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 164 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr164Ala variant is uncertain at this time. References: Link to Sick Kids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html
Illumina Clinical Services Laboratory,Illumina RCV001163277 SCV001325300 uncertain significance CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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