ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3854C>T (p.Ala1285Val)

dbSNP: rs397508617
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000585919 SCV000696994 uncertain significance not specified 2022-04-12 criteria provided, single submitter clinical testing Variant summary: CFTR c.3854C>T (p.Ala1285Val) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 250862 control chromosomes (gnomAD), predominantly at a frequency of 0.0053 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is somewhat lower than the maximum expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (CBAVD) (0.013), allowing no conclusion about variant significance. c.3854C>T has been reported in the literature in at least two Asian Indian individuals affected with CBAVD, however no second (likely) pathogenic variant was specified in these cases (Sachdeva 2011, Gaikwad_2020). The variant was also found during carrier screening in homozygosity in an Asian Indian (Schwartz_2009) and an Australian individual (Archibald_2017), but no phenotype information was provided. These reports do not provide unequivocal conclusions about association of the variant with CBAVD. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance, one as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV001507714 SCV001713438 uncertain significance not provided 2021-07-14 criteria provided, single submitter clinical testing
Invitae RCV000577447 SCV001721256 benign Cystic fibrosis 2024-01-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001507714 SCV002046548 uncertain significance not provided 2022-12-29 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.0053 (162/30594 chromosomes,, is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 21254931 (2011), 34145097 (2020)) and in an individual with pancreatitis (PMID: 33097431 (2020)). The variant has also been reported in carrier screenings (PMID: 19324992 (2009), 29261177 (2018), 30146269 (2019), 32784480 (2020), 32906206 (2020), 33138774 (2020)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Johns Hopkins Genomics, Johns Hopkins University RCV000577447 SCV002051796 likely benign Cystic fibrosis 2021-09-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000577447 SCV002622766 likely benign Cystic fibrosis 2023-04-11 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity RCV001507714 SCV003831650 uncertain significance not provided 2023-04-06 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV003448254 SCV004176470 uncertain significance Hereditary pancreatitis 2023-03-01 criteria provided, single submitter clinical testing The missense c.3854C>T (p.Ala1285Val) variant in CFTR gene has been reported previously in heterozygous state in individual(s) affected with SPINK1-associated Chronic Pancreatitis (Jones et al., 2020). This variant is reported with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database with varying interpretation: Benign / Likely Benign / Uncertain Significance (multiple submitters). The amino acid Ala at position 1285 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala1285Val in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. SPINK1 carriers with co-occurring mutations in CFTR exhibited prominent fibrosis of the pancreas and only focal intralobular and/or extralobular lipomatous infiltration into the pancreatic parenchyma. For these reasons, this variant has been classified as Uncertain Significance.
PreventionGenetics, part of Exact Sciences RCV004537230 SCV004720028 likely benign CFTR-related disorder 2022-02-09 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577447 SCV000679387 not provided Cystic fibrosis no assertion provided literature only
Natera, Inc. RCV000577447 SCV001460116 uncertain significance Cystic fibrosis 2017-05-09 no assertion criteria provided clinical testing

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