ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2930C>T (p.Ser977Phe) (rs141033578)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755913 SCV000883568 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing The CFTR c.2930C>T, p.Ser977Phe variant (rs141033578) has been reported in patients diagnosed with cystic fibrosis (Le Marechal 2001) and CFTR-related disorders (Lebecque 2002, Ratbi 2007, Sorio 2013, Trujillano 2013, Tzetis 2001). It was identified in-cis with the pathogenic 12TG-5T variant in multiple individuals (Lebecque 2002, Sorio 2013, Trujillano 2013, Tzetis 2001); therefore, it is possible that p.Ser977Phe and 12TG-5T could represent a complex allele if found together. Functional characterization of the p.Ser977Phe variant indicates wildtype levels of CFTR expression and protein maturation, but the variant protein has a chloride transport activity at 5 percent of wildtype CFTR (Van Goor 2014, CFTR2 database). Due to the variability of associated clinical phenotype, the p.Ser977Phe variant has been described as a variant of indeterminate or varying clinical consequence by the CFTR2 variant database (Sosnay 2013, CFTR2 database). The variant is listed in ClinVar (Variation ID: 53601), and observed in the general population databases at a frequency of 0.0077 percent in the Exome Variant Server (1/12990 alleles), and 0.001 percent in the Genome Aggregation Database (3/245914 alleles). The serine at residue 977 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Due to the conflicting information regarding this variant, its clinical significance could not be determined with certainty. References: CFTR2 database: http://cftr2.org/ Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001; 108(4):290-8. Lebecque P et al. Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Am J Respir Crit Care Med. 2002; 165(6):757-61. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007; 22(5):1285-91. Sorio C et al. Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation. J Cyst Fibros. 2013; 12(6):821-5. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013; 50(7):455-62. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet. 2001; 108(3):216-21. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577087 SCV000679033 not provided Cystic fibrosis no assertion provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000780158 SCV000917206 likely pathogenic not specified 2018-05-09 criteria provided, single submitter clinical testing Variant summary: CFTR c.2930C>T (p.Ser977Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain 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 1.2e-05 in 246018 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (1.2e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.2930C>T, has been reported in the literature in individuals affected with Non-classic Cystic Fibrosis, CBAVD, ICP, and classic CF. These data indicate that the variant may be associated with disease. The variant has been observed multiple times in cis with c.5T_TG12, a well known pathogenic variant. A reputable database, CFTR2, reports the variant to have been observed in both patients with this variant, combined with another CF-causing variant that have CF and patients with this variant combined with another CF causing variant that do not have CF. However, a functional study, Van Goor_2014, found the variant to significantly decrease Cl- transport. 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 likely pathogenic.
PharmGKB RCV000660775 SCV000783014 drug response ivacaftor response - Efficacy 2018-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.

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