ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.929TCT[2] (p.Phe312del)

dbSNP: rs121908768
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000759769 SCV000331527 pathogenic not provided 2013-11-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047290 SCV000697058 pathogenic Cystic fibrosis 2022-01-10 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759769 SCV000889318 pathogenic not provided 2017-10-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000759769 SCV001160472 likely pathogenic not provided 2020-06-19 criteria provided, single submitter clinical testing The CFTR c.935_937delTCT; p.Phe312del variant (rs121908768), also known as F311del, is reported in the literature in multiple individuals affected with cystic fibrosis and has been found in affected individuals in trans to the pathogenic p.Phe508del variant (Friedman 1998, Meitinger 1993). The p.Phe312del variant is also frequently observed in African-American and Hispanic cystic fibrosis patients (Kharrazi 2015, Schrijver 2005, Sugarman 2004, Watts 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 48704) and 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. This variant deletes a highly conserved phenylalanine residue, leaving the rest of the protein in-frame. Based on available information, the p.Phe312del variant is considered to be likely pathogenic. REFERENCES Friedman K et al. Cystic fibrosis transmembrane-conductance regulator mutations among African Americans. Am J Hum Genet. 1998 62(1):195-6. Kharrazi M et al. Newborn Screening for Cystic Fibrosis in California. Pediatrics. 2015 Dec;136(6):1062-72. 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. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 May;7(2):289-99. Sugarman EA et al. CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations. Genet Med. 2004 Sep-Oct;6(5):392-9. Watts KD et al. Hispanic Infants with cystic fibrosis show low CFTR mutation detection rates in the Illinois newborn screening program. J Genet Couns. 2012 Oct;21(5):671-5.
Baylor Genetics RCV001004242 SCV001163118 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000047290 SCV001582745 pathogenic Cystic fibrosis 2023-10-14 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000759769 SCV002525766 pathogenic not provided 2022-11-15 criteria provided, single submitter clinical testing PP5, PM3, PM4
Ambry Genetics RCV000047290 SCV002686349 pathogenic Cystic fibrosis 2022-01-31 criteria provided, single submitter clinical testing The p.F312del pathogenic mutation (also known as c.935_937delTCT, c.933_935delCTT and deltaF311 in the literature) is located in coding exon 8 of the CFTR gene. This mutation results from an in-frame deletion of 3 nucleotides at positions 935 to 937. This results in the deletion of a phenylalanine (F) residue at codon 312, within a string of F residues (codons 310 through 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity RCV000759769 SCV003826302 likely pathogenic not provided 2022-08-23 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000047290 SCV004024540 likely pathogenic Cystic fibrosis 2023-07-14 criteria provided, single submitter clinical testing CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.
Baylor Genetics RCV003473298 SCV004213347 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2024-03-19 criteria provided, single submitter clinical testing
Counsyl RCV000047290 SCV001132361 likely pathogenic Cystic fibrosis 2017-05-26 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004734591 SCV005362944 pathogenic CFTR-related disorder 2024-06-27 no assertion criteria provided clinical testing 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.

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