rs121908768

Variant names:

• chr7-117540156-CCTT-C
• rs121908768
• NM_000492.4:c.935_937delTCT

Your query was ambiguous. Multiple possible variants found:

• chr7-117540156-CCTT-C
• chr7-117540156-CCTT-CCTTCTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_000492.4(CFTR):​c.935_937delTCT​(p.Phe312del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,440 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: CFTR NM_000492.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.54
• Publications: 5 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 31 uncertain in NM_000492.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000492.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-117540156-CCTT-C is Pathogenic according to our data. Variant chr7-117540156-CCTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 48704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.935_937delTCT	p.Phe312del	disruptive_inframe_deletion	Exon 8 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.935_937delTCT	p.Phe312del	disruptive_inframe_deletion	Exon 8 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000757 AC: 19 AN: 251076 AF XY: 0.0000442

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461234 Hom.: 1 AF XY: 0.0000371 AC XY: 27 AN XY: 726948

African (AFR) AF: 0.000149 AC: 5 AN: 33470

American (AMR) AF: 0.000336 AC: 15 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111450

Other (OTH) AF: 0.0000497 AC: 3 AN: 60366

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74406

African (AFR) AF: 0.000169 AC: 7 AN: 41516

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:6

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 26, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jan 10, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jul 14, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:5

Jun 19, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Nov 19, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 15, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM3, PM4

Oct 12, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 23, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR-related disorder Pathogenic:1

Jun 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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.

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=48/52	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908768; hg19: chr7-117180210;