rs121908769

Positions:

• chr7-117509127-CTT-C
• chr7-117509127-CTT-CTTTT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.262_263del​(p.Leu88IlefsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.000122 in 1,579,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117509127-CTT-C is Pathogenic according to our data. Variant chr7-117509127-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 7232.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117509127-CTT-C is described in Lovd as [Pathogenic]. Variant chr7-117509127-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.262_263del	p.Leu88IlefsTer22	frameshift_variant	3/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.262_263del	p.Leu88IlefsTer22	frameshift_variant	3/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 250824 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 170 AN: 1427184 Hom.: 0 AF XY: 0.000124 AC XY: 88 AN XY: 712528

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00190

Gnomad4 NFE exome AF: 0.0000518

Gnomad4 OTH exome AF: 0.000203

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 15, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CFTR: PM3:Very Strong, PVS1, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 20, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2023	Observed multiple times with a pathogenic variant in unrelated patients with cystic fibrosis or a CFTR-related disorder in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 7509311, 22678879, 28603918, 23974870); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as 394delTT; This variant is associated with the following publications: (PMID: 14872121, 34996830, 31036917, 22975760, 22658665, 7691344, 752596, 9259197, 22678879, 26087176, 16051530, 18456578, 29261177, 32429104, 31589614, 34782259, 23974870, 7509311, 28603918) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 22, 2015	- -

Cystic fibrosis Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 19, 2021	The c.262_263delTT pathogenic mutation, located in coding exon 3 of the CFTR gene, results from a deletion of two nucleotides at positions 262 to 263, causing a translational frameshift with a predicted alternate stop codon (p.L88Ifs*22). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7, Supplementary Table). In one study, this mutation reportedly accounted for 8.5% of cystic fibrosis (CF) mutations in a cohort of 331 CF patients from Sweden (Schaedel C, et al. Clin.Genet.1999;56(4):318-22). This mutation was also reportedly detected in the homozygous state in an infant with severe CF manifestations including pancreatic insufficiency, anemia, failure to thrive, elevated sweat chloride level, and severe pulmonary disease (Kahre T et al. J.Cyst.Fibros.2004;3(1):58-60). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 07, 2020	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2017	Variant summary: The CFTR c.262_263delTT (p.Leu88Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.p.Glu193X, p.Gln220X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 39/121142 control chromosomes at a frequency of 0.0003219, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in a large number of CF patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	NM_000492.3(CFTR):c.262_263delTT(L88Ifs*22, aka 394delTT) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.262_263delTT(L88Ifs*22, aka 394delTT) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	This sequence change creates a premature translational stop signal (p.Leu88Ilefs*22) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs754147777, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis and CFTR-related conditions (PMID: 7691344, 22658665, 23378603, 23974870). This variant is also known as 394delTT. ClinVar contains an entry for this variant (Variation ID: 7232). For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 16, 2016

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908769; hg19: chr7-117149181;