ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.794T>G (p.Met265Arg) (rs148519623)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282818 SCV000603052 likely pathogenic none provided 2019-07-31 criteria provided, single submitter clinical testing The CFTR c.794T>G; p.Met265Arg variant (rs148519623) reported is reported in the literature in a newborn with meconium ileus (SickKids CFTR database) and in individuals with congenital bilateral absence of vas deferens or pancreatitis (Dork 1997, Goossens 2000). At least three affected individuals were also observed to carry the pathogenic p.Phe508del variant (SickKids CFTR database, Dork 1997, Goossens 2000). The p.Met265Arg variant is also reported in seven individuals in the CFTR2 database (see link) that also carried a second pathogenic variant, of whom the majority were pancreatic-insufficient. The p.Met265Arg variant is found on only four chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. In functional assays, the variant protein exhibits only 19% of wildtype CFTR chloride channel activity (Raraigh 2018). Based on available information, this variant is considered to be likely pathogenic. References: CFTR2 database: https://cftr2.org/ SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=156 Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997; 100(3-4):365-77. Goossens V et al. Clinical application of preimplantation genetic diagnosis for cystic fibrosis. Prenat Diagn. 2000 Jul;20(7):571-81. 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 RCV000671208 SCV000796161 uncertain significance Cystic fibrosis 2017-12-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000671208 SCV000917193 likely pathogenic Cystic fibrosis 2021-08-31 criteria provided, single submitter clinical testing Variant summary: CFTR c.794T>G (p.Met265Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 1.2e-05 in 245598 control chromosomes. c.794T>G has been reported in the literature as a compound heterozygous genotype with p.F508del in individuals affected with features resembling Non-Classic Cystic Fibrosis ranging from CBAVD (example, Dork_1997, Goossens_2000), pancreatic insufficiency and intermediate levels of sweat chloride (example, McCague_2019). As of now, there are 7 patients with this variant in the CFTR2 database and it was annotated as a variant with varying clinical consequences, i.e. some patients with this variant, combined with another CF-causing variant, have CF, while other patients do not have CF. Because of this variability, it is very important that clinical criteria alone be used to determine whether a person with this variant has CF. These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absent plasma membrane expression as measured by a cell surface ELISA assay in BHK cells (Okiyoneda_2013) and reduced CFTR function as assessed by a short circuit current measurement assay (Raraigh_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Both submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV001004238 SCV001163114 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000671208 SCV001822023 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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