Variant summary: CFTR c.935_937delTCT (p.Phe312del) results in an in-frame deletion that is predicted to remove one phenylalanine from three consecutive phenylalanines, located in the first transmembrane region (IPR011527) of the encoded protein. The variant allele was found at a frequency of 7.6e-05 in 251076 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013), allowing no conclusion about variant significance. The variant (also known as deltaF311) has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Meitinger_1993, Friedman_1998, Heim_2001, Watts_2012, Kharrazi_2015, Taccetti_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (n=2) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

PP5, PM3, PM4

The c.935_937delTCT variant in CFTR is an in-frame deletion predicted to remove phenylalanine at amino acid 312 while preserving the reading frame. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in at least one unaffected individual, with a zygosity that is consistent with the inheritance pattern for the associated condition (in gnomAD and/or literature). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 37477516, 35313924, 7509232, 26574590, 9443874, 16980811, 32630227). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic.

The c.935_937delTCT pathogenic mutation (also known as p.F312del) is located in coding exon 8 of the CFTR gene. This pathogenic mutation results from an in-frame TCT deletion at nucleotide positions 935 to 937. This results in the in-frame deletion of a phenylalanine at codon 312. In a meta-analysis of worldwide mutation incidence, this mutation was observed in 0.2% of all cystic fibrosis (CF) alleles, and in 2.0% of African American CF alleles (Bobadilla JL et al. Hum. Mutat. 2002;19(6):575-606). In one study, this mutation was detected in trans with p.F508del in a 2-year-old patient with growth retardation who was noted to have repeated elevated sweat chloride levels, but unremarkable lung and gastrointestinal symptoms (Meitinger T et al. Hum Mol Genet. 1993;2(12):2173-2174). Another study detected this mutation in a Hispanic CF patient, but no further clinical data was provided (Schrijver I et al. J Mol Diagn. 2005;7(2):289-299). We have observed this mutation in either the homozygous or compound heterozygous state in CF patients in our clinical cohort. In addition, our internal structural analysis revealed that F312 is a part of the transmembrane loop 5 and loss of this residue results in disruptive shift of amino acids in the loop (Zhang Z et al. Cell, 2016 Dec;167:1586-1597.e9). Note, this variant is also referred to as c.933_935delCTT and deltaF311 in the literature. This amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.;For recessive disorders, detected in trans with a pathogenic variant.

This variant, c.935_937del, results in the deletion of 1 amino acid(s) of the CFTR protein (p.Phe312del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758477732, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with cystic fibrosis (PMID: 7509232, 9443874, 16980811, 26098992). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as deltaF311. ClinVar contains an entry for this variant (Variation ID: 48704). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.

CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.

The CFTR c.935_937delTCT; p.Phe312del variant (rs121908768, ClinVar Variation ID: 48704), also known as F311del, is reported in the literature in the compound heterozygous state with a CF-causing variant or a mild variant in individuals affected with cystic fibrosis (CF), and also in an individual with congenital absence of the vas deferens (Ang 2023, Fang 2022, Friedman 1998, Kharrazi 2015, Meitinger 1993, Raraigh 2022, Xu 2023). In patients with another with a CF-causing variant, lung function is typically normal, sweat chloride levels are elevated, and pancreatic sufficiency is variable (CFTR2 database, Eastman 2024). This variant is found in the general population with an overall allele frequency of 0.008% (19/251076 alleles, including one homozygote) in the Genome Aggregation Database (v2.1.1). This variant deletes a single phenylalanine residue, leaving the rest of the protein in-frame. Based on available information including the phenotypic variability, the p.Phe312del variant is considered to be likely pathogenic with varying clinical consequences. References: Link to CFTR2 database: https://cftr2.org/ Ang B et al. Biliary Atresia and Rare Concurrent Cystic Fibrosis Variant: Case Report and Management Considerations. JPGN Rep. 2023 Jan 30;4(1):e285. PMID: 37181919. Fang J et al. Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations. Front Genet. 2022 Nov 9;13:1035468. PMID: 36437957. Friedman K et al. Cystic fibrosis transmembrane-conductance regulator mutations among African Americans. Am J Hum Genet. 1998 62(1):195-6. PMID: 9443874. Kharrazi M et al. Newborn Screening for Cystic Fibrosis in California. Pediatrics. 2015 Dec;136(6):1062-72. PMID: 26574590. Meitinger T et al. In frame deletion (delta F311) within a short trinucleotide repeat of the first transmembrane region of the cystic fibrosis gene. Hum Mol Genet. 1993 2(12):2173-4. PMID: 7509232. Raraigh KS et ak. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022 May;21(3):463-470. PMID: 34782259. Xu C et al. Clinical and genetic characteristics of children with cystic fibrosis in Henan China: A single-center retrospective analysis. Pediatr Pulmonol. 2023 Oct;58(10):2865-2870. PMID: 37477516.

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The CFTR c.935_937delTCT variant is predicted to result in an in-frame deletion (p.Phe312del). This variant, also referred to as p.Phe311del, has previously been reported to be causative for cystic fibrosis (Friedman et al. 1998. PubMed ID: 9443874; Bobadilla et al. 2002. PubMed ID: 12007216; Kammesheidt et al. 2006. PubMed ID: 16980811; Kay et al. 2015. PubMed ID: 26098992; Schrijver et al. 2016. PubMed ID: 26708955). This variant is reported in 0.035% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.