rs397508571

chr7-117530971-G-Achr7-117530971-G-C

Variant summary

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

The NM_000492.4(CFTR):c.346G>A(p.Glu116Lys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E116Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 9.52

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 7-117530971-G-A is Pathogenic according to our data. Variant chr7-117530971-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53754.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.346G>A	p.Glu116Lys	missense_variant	4/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.346G>A	p.Glu116Lys	missense_variant	4/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Other:1

Pathogenic, reviewed by expert panel	research	CFTR2	Sep 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 02, 2023	Variant summary: CFTR c.346G>A (p.Glu116Lys) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251008 control chromosomes. c.346G>A has been reported in the literature in a homozygous patient suspected of Cystic Fibrosis (Schrijver_2005) and compound heterozygous patients with Cystic Fibrosis and related conditions (Brugel_2010 and Sickkids_database). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating reduced transport of mature CFTR protein to cell surface and destabalization of the open state of chloride channel (Hammerle_2001) and severely reduced functionality (Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 19843100, 11278813, 30888834, 29805046, 15858154, Sickkids_database).Five 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 (n=3) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 19, 2015	The p.E116K variant (also known as c.346G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 346. The glutamic acid at codon 116 is replaced by lysine, an amino acid with similar properties. This pathogenic alteration was described in the homozygous state in one individual in a Hispanic population, but specific clinical information was not reported (Schrijver et al. J Mol Diagn 2005 May; 7(2):289-99 ). In vitro studies demonstrated that this alteration affects protein chloride channel current and transport to the cell membrane (Cui et al. J Gen Physiol. 2014;144(2):159-79; Hammerle et al. J. Biol. Chem. 2001 May; 276(18):14848-54; Lu et al. J. Biol. Chem. 1998 Jan; 273(1):568-76). In addition, this variant has been detected in conjunction with a pathogenic alteration in CFTR several times by our laboratory to date. This variant is unknown to be in cis or trans with these known pathogenic alterations. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 02, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 11278813, 29805046, 30046002). 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 expected to disrupt CFTR protein function. ClinVar contains an entry for this variant (Variation ID: 53754). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 15858154, 19843100; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 116 of the CFTR protein (p.Glu116Lys). -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 18, 2021

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 30, 2018

The CFTR c.346G>A; p.Glu116Lys variant (rs397508571) has been described in the compound heterozygous state in individuals with mild cystic fibrosis and allergic bronchopulmonary aspergillosis, and in the homozygous state in one individual with a CFTR-related disorder with unknown clinical phenotype (see link to SickKids database, Burgel 2010, Schrijver 2005). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 116 is highly conserved, but computational algorithms (PolyPhen-2: probably damaging, SIFT: tolerated) are inconclusive on the effects of this variant on protein structure and/or function. Functional studies demonstrate destabilization of the open state of the chloride channel and slightly reduced transport of mature CFTR protein to the cell surface (Hammerle 2001). Based on available information, this variant is considered likely pathogenic. References: SickKids Databse: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=87 Burgel P et al. Non-classic cystic fibrosis associated with D1152H CFTR mutation. Clin Genet. 2010 Apr;77(4):355-64. Hammerle M et al. Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. J Biol Chem. 2001 May 4;276(18):14848-54. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D;N;.;.;N;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;T;.;.;T;.
Sift4G	Pathogenic	0.0	D;D;.;.;D;.
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.95
MutPred		0.88		.;Gain of methylation at E116 (P = 0.0016);Gain of methylation at E116 (P = 0.0016);Gain of methylation at E116 (P = 0.0016);Gain of methylation at E116 (P = 0.0016);Gain of methylation at E116 (P = 0.0016);
MVP		1.0
MPC		0.0084
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.95

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: rs397508571; hg19: chr7-117171025; COSMIC: COSV50048108;