7-117610598-T-G

Position:

• chr7-117610598-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000003084.11(CFTR):​c.3068T>G​(p.Ile1023Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFTR ENST00000003084.11 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.94

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]

ENSG00000083622 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000003084.11
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 7-117610598-T-G is Pathogenic according to our data. Variant chr7-117610598-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3068T>G	p.Ile1023Arg	missense_variant	19/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3068T>G	p.Ile1023Arg	missense_variant	19/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251076 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	NxGen MDx	May 19, 2020	This missense variant (c.3068T>G) in a hotspot on exon 19 of CFTR (PM1) and gnomAD databases indicate low allele frequency (PM2). Computational models produce mostly pathogenic verdicts for this variant (PP3). This variant has been reported in heterozygosity with c.1898+5G>T in two Taiwanese brothers with recurrent pneumonia and bronchiolitis. One of the brothers had sweat chloride levels >100 meq/l indicating a diagnosis of cystic fibrosis (Chen el al. PMID 23089694; Liu et al. PMID 22992393). There are 4 additional cases in Leung et al. PMID 28116329 where the authors suggest this variant may be a founder mutation in southern Han Chinese. Leung et al. also conducted functional analysis demonstrating that p.Ile1023Arg leads to a trafficking defect during CFTR maturation without affecting the gating function. We interpret c.3068T>G to be likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 07, 2019	The p.I1023R variant (also known as c.3068T>G), located in coding exon 19 of the CFTR gene, results from a T to G substitution at nucleotide position 3068. The isoleucine at codon 1023 is replaced by arginine, an amino acid with similar properties. This variant has been identified in several individuals with symptoms of cystic fibrosis with a second CFTR variant and has been suggested to be a Southern Chinese founder mutation (Chen CH et al. J. Formos. Med. Assoc., 2012 Oct;111:580-3; Liu LC et al. J Microbiol Immunol Infect, 2014 Aug;47:358-61; Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). One homozygous individual presented at 4 months of age with elevated sweat chloride levels, respiratory symptoms, and pancreatic insufficiency (Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). In HeLa cells, this variant demonstrated reduced levels of mature CFTR protein compared to wild type (Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 28116329). ClinVar contains an entry for this variant (Variation ID: 495923). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 22992393, 23089694, 28116329). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs756219310, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1023 of the CFTR protein (p.Ile1023Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2024	Variant summary: CFTR c.3068T>G (p.Ile1023Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251076 control chromosomes. c.3068T>G has been reported in the literature in the presumed compound heterozygous, compound heterozygous, or homozygous states multiple individuals affected with Cystic Fibrosis (example, Leung_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 1.73% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 23089694, 28116329, 22992393, 38388235). ClinVar contains an entry for this variant (Variation ID: 495923). Based on the evidence outlined above, the variant was classified as pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.71	N;.;.;N;.
REVEL	Uncertain	0.57
Sift	Benign	0.052	T;.;.;D;.
Sift4G	Uncertain	0.030	D;.;.;D;.
Polyphen		0.77	P;.;.;.;.
Vest4		0.70
MutPred		0.93		Gain of methylation at I1023 (P = 0.0026);.;.;.;.;
MVP		1.0
MPC		0.0048
ClinPred		0.56	D
GERP RS		6.2
Varity_R		0.68
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs756219310; hg19: chr7-117250652;