ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1046C>T (p.Ala349Val) (rs121909021)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000780115 SCV000603017 pathogenic not specified 2019-04-08 criteria provided, single submitter clinical testing The CFTR c.1046C>T; p.Ala349Val variant (rs121909021) has been reported in patients diagnosed with congenital bilateral absence of vas deferens (Dayangac 2004, Havasi 2010) or pancreatitis (Keiles 2006, Sultan 2010), when found in-trans with pathogenic CFTR variants (Dayangac 2004, Sultan 2012). Functional studies show this variant to have approximately 45% of wild type function (Raraigh 2018). This variant is reported in ClinVar (Variation ID: 7172). It is found in the general population with an overall allele frequency of 0.01% (32/282468 alleles) in the Genome Aggregation Database. The alanine at codon 349 is weakly conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Due to its reported occurrence in CFTR-related disorders, the p.Ala349Val variant is classified as mildly pathogenic. REFERENCES Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. Havasi V et al. Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens. Fertil Steril. 2010 Nov;94(6):2122-7. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Sultan M et al. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. 2012 May;54(5):645-50. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077.
Counsyl RCV000007592 SCV000800525 uncertain significance Cystic fibrosis 2017-05-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728852 SCV000856470 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000728852 SCV000888065 likely pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780115 SCV000917159 uncertain significance not specified 2019-10-15 criteria provided, single submitter clinical testing Variant summary: CFTR c.1046C>T (p.Ala349Val) results in a non-conservative amino acid change located in the ABC transporter transmembrane region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251726 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00011 vs 0.013), allowing no conclusion about variant significance. c.1046C>T has been reported in the literature in individuals affected with Cystic Fibrosis, chronic pancreatis, and CBAVD. These data indicate that the variant may be associated with disease. Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Raraigh_2018, Han_2018). A reputable database (CFTR2) stated that there is not enough information to determine whether or not A349V causes CF. Five ClinVar submissions (evaluation after 2014) cites the variant as pathogenic twice, once as likely pathogenic and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV001004253 SCV001163129 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000007592 SCV001425410 uncertain significance Cystic fibrosis 2020-05-22 criteria provided, single submitter clinical testing CFTR variant of uncertain clinical significance. See for phenotype information.
OMIM RCV000007592 SCV000027793 pathogenic Cystic fibrosis 2016-12-08 no assertion criteria provided literature only

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