ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1454G>C (p.Ser485Thr) (rs143980575)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001095217 SCV000466514 uncertain significance CFTR-related disorders 2018-01-13 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000592449 SCV000700531 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing
Invitae RCV000361103 SCV000944946 uncertain significance Cystic fibrosis 2019-03-19 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 485 of the CFTR protein (p.Ser485Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs143980575, ExAC 0.003%). This variant has not been reported in the literature in individuals with CFTR-related disease. ClinVar contains an entry for this variant (Variation ID: 358731). 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 RCV001001194 SCV001158353 uncertain significance not specified 2019-04-07 criteria provided, single submitter clinical testing The CFTR c.1454G>C; p.Ser485Thr variant (rs143980575) is reported in the SickKids database in association with a suspected diagnosis of CF but no specific details were provided (see link). This variant is reported as uncertain significance in ClinVar (Variation ID: 358731). A different variant at this codon, p.Ser485Cys, is reported in the literature in an individual with congenital bilateral absence of vas deferens who also carries the pathogenic mild 5T allele (Li 2012). The p.Ser485Thr variant is found in the general population with a low overall allele frequency of 0.005% (14/282718 alleles) in the Genome Aggregation Database. The serine at codon 485 is highly conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Probably Damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Link to SickKids database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1871 Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 Jul;11(4):316-23.
Integrated Genetics/Laboratory Corporation of America RCV001001194 SCV001360595 uncertain significance not specified 2019-11-29 criteria provided, single submitter clinical testing Variant summary: CFTR c.1454G>C (p.Ser485Thr) results in a conservative amino acid change located in the ABC transporter-like (IPR003439)and AAA+ ATPase domains (IPR003593) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251332 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (5.2e-05 vs 0.013), allowing no conclusion about variant significance. c.1454G>C has been reported in the literature in individuals affected with pancreatic cancer and pancreatitis (Tamura _2018, Shik Mun _2019). These reports however, do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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