Submissions for variant NM_000492.4(CFTR):c.3700A>G (p.Ile1234Val)

dbSNP: rs75389940

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007636	SCV000245876	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000007636	SCV000886213	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CFTR-France	RCV000007636	SCV001169356	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269696	SCV001449885	pathogenic	not provided	2017-01-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001269696	SCV001470500	pathogenic	not provided	2020-04-17	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Baylor Genetics	RCV000007636	SCV001523285	pathogenic	Cystic fibrosis	2020-06-10	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007636	SCV001586454	pathogenic	Cystic fibrosis	2024-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1234 of the CFTR protein (p.Ile1234Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs75389940, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10605524, 11336127, 15698946, 15948195, 21909392, 25593612, 26096753). ClinVar contains an entry for this variant (Variation ID: 7215). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 15480987, 24556927, 25735457). Studies have shown that this missense change results in the activation of a cryptic splice site in exon 19 (PMID: 15480987, 24556927, 25735457). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001269696	SCV001713432	pathogenic	not provided	2019-07-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007636	SCV002624131	pathogenic	Cystic fibrosis	2017-01-12	criteria provided, single submitter	clinical testing	The p.I1234V pathogenic mutation (also known as c.3700A>G), located in coding exon 22 of the CFTR gene, results from an A to G substitution at nucleotide position 3700. The isoleucine at codon 1234 is replaced by valine. This mutation is the second most common CF-causing mutation in the Middle East (Molinski SV et al. Genet Med. 2014;16(8):625-32). This alteration was first described in an individual who was diagnosed with cystic fibrosis (CF) at 2 years of age and also carried the p.F508del mutation (Claustres M et al. Hum Mutat. 1992;1(4):310-3). In a large cohort of individuals homozygous for this mutation, this mutation was associated with pancreatic sufficiency (Abdel Rahman H et al. Acta Paediatr. 2006;95(9):1066-9). An in vitro functional study using reverse transcriptase-PCR found this mutation activates a cryptic donor splice site and results in the deletion of six amino acids (p.I1234_R1239del); this deletion causes a primary defect in protein folding and processing, similar to p.F508del but less severe (Molinski SV et al. Genet Med. 2014;16(8):625-32). A later study confirmed the alternative splicing described, through both an ex vivo study of RNA levels in nasal and colon epithelial cells from a CF patient, and a minigene assay using BHK cells. Furthermore, functional analysis showed reduced chloride channel function by the mutant protein (Ramalho AS, J. Cyst. Fibros. 2016 Jan; 15(1):21-33). Based on the supporting evidence, p.I1234V is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV001269696	SCV003826269	likely pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007636	SCV003844257	pathogenic	Cystic fibrosis	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3700A>G (p.Ile1234Val) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by activating a cryptic donor splice site 18bp upstream of the original donor splice site, resulting in deletion of six amino acids (Molinski_2014). The variant allele was found at a frequency of 4e-06 in 249440 control chromosomes. c.3700A>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Example: Claustres_1992, Abdul Wahab_2014, Wei_2006, Sosnay_2013 etc.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports significantly impaired CFTR function (Molinski_2014). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000007636	SCV004805192	pathogenic	Cystic fibrosis	2024-03-17	criteria provided, single submitter	research
Baylor Genetics	RCV004566693	SCV005057468	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-12-02	criteria provided, single submitter	clinical testing
OMIM	RCV000007636	SCV000027837	pathogenic	Cystic fibrosis	1993-01-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000007636	SCV001133028	pathogenic	Cystic fibrosis	2019-09-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831553	SCV002075868	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831553	SCV004115658	pathogenic	CFTR-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The CFTR c.3700A>G variant is predicted to result in the amino acid substitution p.Ile1234Val. This variant has been reported in numerous patients with cystic fibrosis or CFTR-associated phenotypes (Hirtz et al. 2004. PubMed ID: 15480987; Wei et al. 2006. PubMed ID: 16617247; Molinski et al. 2014. PubMed ID: 24556927; El Bar Aluma et al. 2020. PubMed ID: 32843167). Functional studies showed that this variant alters splicing by activating an alternative splice site leading to a deletion of six amino acids and impacts protein function (Hirtz et al. 2004. PubMed ID: 15480987; Molinski et al. 2014. PubMed ID: 24556927; Ramalho et al. 2016. PubMed ID: 25735457). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.