rs75389940

chr7-117627753-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):c.3700A>G(p.Ile1234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 3.29

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 67 pathogenic changes around while only 7 benign (91%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117627753-A-G is Pathogenic according to our data. Variant chr7-117627753-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7215.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117627753-A-G is described in Lovd as [Pathogenic]. Variant chr7-117627753-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3700A>G	p.Ile1234Val	missense_variant	22/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3700A>G	p.Ile1234Val	missense_variant	22/27	1	NM_000492.4	P2
	ENST00000456270.1	n.66-11413T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248702 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134526

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: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459770 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 10, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 12, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2023	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. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 03, 2019	- -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 04, 2023	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 (http://gnomad.broadinstitute.org/variant/7-117267807-A-G). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Uncertain	0.55	D;.;.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Uncertain	0.043	D
MutationAssessor	Benign	0.28	N;.;.;.;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.50	N;.;.;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.19	T;.;.;T;.
Sift4G	Benign	0.94	T;.;.;T;.
Polyphen		0.0010	B;.;.;.;.
Vest4		0.25
MutPred		0.81		Loss of catalytic residue at P1236 (P = 0.0309);.;.;.;.;
MVP		0.93
MPC		0.0044
ClinPred		0.24	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: -1
DS_DL_spliceai		0.49		Position offset: 17

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

Publications

LitVar

Other links and lift over

dbSNP: rs75389940; hg19: chr7-117267807;