chr7-117540231-G-T

Position:

chr7-117540231-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.1001G>T(p.Arg334Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R334Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 7.60

Variant links:

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]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 18) in uniprot entity CFTR_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117540231-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 7-117540231-G-T is Pathogenic according to our data. Variant chr7-117540231-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 53160.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117540231-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1001G>T	p.Arg334Leu	missense_variant	8/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1001G>T	p.Arg334Leu	missense_variant	8/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74262

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_VSTR, PM5_STR, PP3, PP4 -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 2024	The p.R334L pathogenic mutation (also known as c.1001G>T), located in coding exon 8 of the CFTR gene, results from a G to T substitution at nucleotide position 1001. The arginine at codon 334 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in a male with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with a second CFTR alteration; however, the phase was not provided (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). Two disease-causing mutations, p.R334W and p.R334Q, have been described in the same codon. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 14, 2023	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 334 of the CFTR protein (p.Arg334Leu). This variant is present in population databases (rs397508137, gnomAD 0.007%). This missense change has been observed in individuals with CFTR-related conditions (PMID: 9272157, 27157324, 30134826). ClinVar contains an entry for this variant (Variation ID: 53160). 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 C15"). Experimental studies have shown that this missense change affects CFTR function (PMID: 12679372, 15130785, 17673962, 30046002). This variant disrupts the p.Arg334 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15371902, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2018	- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2024

The CFTR c.1001G>T variant is predicted to result in the amino acid substitution p.Arg334Leu. This variant is known to disrupt protein function and has been documented as causative for cystic fibrosis (CF) and CF-related disorders (Dörk et al. 1997. PubMed ID: 9272157; Sosnay et al. 2013. PubMed ID: 23974870; Lucarelli et al. 2015. PubMed ID: 25910067; Raraigh et al. 2018. PubMed ID: 29805046; Sofia et al. 2018. PubMed ID: 30134826). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. An alternative nucleotide change affecting the same amino acid (p.Arg334Trp) is a well-established cause of CF and CF-related disorders (Gasparini et al. 1991. PubMed ID: 2045102; Sheppard et al. 1993. PubMed ID: 7680769; Maisonneuve et al. 2004. PubMed ID: 15181620; Watson et al. 2004. PubMed ID: 15371902; Lucarelli et al. 2015. PubMed ID: 25910067; Karimi et al. 2018. PubMed ID: 29850441). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 19, 2019

The CFTR c.1001G>T; p.Arg334Leu variant (rs397508137) is reported in the compound heterozygous state with another pathogenic variant in individuals with pancreatic insufficient cystic fibrosis (see link to CFTR2 database), and in at least one individual affected with congenital bilateral absence of vas deferens (Dork 1997). This variant is reported in ClinVar (Variation ID: 53160), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 334 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.1000C>T; p.Arg334Trp) has been reported in individuals with cystic fibrosis, and is considered pathogenic (Sosnay 2013). Functional assays show that residue 334 is critical for ion binding, and variants at this codon, including p.Arg334Leu, disrupt channel function (Enquist 2009, Gong 2003, Gong 2004, Raraigh 2018, Zhou 2007). Based on available information, the p.Arg334Leu variant is considered to be pathogenic. References: Link to CFTR2 database: https://www.cftr2.org Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 100(3-4):365-77. Enquist K et al. Membrane-integration characteristics of two ABC transporters, CFTR and P-glycoprotein. J Mol Biol. 2009 Apr 17;387(5):1153-64. Gong X and Linsdell P. Molecular determinants and role of an anion binding site in the external mouth of the CFTR chloride channel pore. J Physiol. 2003 Jun 1;549(Pt 2):387-97. Gong X and Linsdell P. Maximization of the rate of chloride conduction in the CFTR channel pore by ion-ion interactions. Arch Biochem Biophys. 2004 Jun 1;426(1):78-82. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. Zhou JJ et al. Direct and indirect effects of mutations at the outer mouth of the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Membr Biol. 2007 Apr;216(2-3):129-42. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 20, 2024

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Sep 12, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;T;.

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.61

MutationAssessor

Uncertain

2.1

M;.;.;.;M

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.5

N;.;.;N;.

REVEL

Pathogenic

0.73

Sift

Benign

0.046

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.88

MutPred

0.93

Loss of MoRF binding (P = 0.0315);Loss of MoRF binding (P = 0.0315);Loss of MoRF binding (P = 0.0315);.;Loss of MoRF binding (P = 0.0315);

MVP

0.97

MPC

0.0048

ClinPred

0.98

GERP RS

4.5

Varity_R

0.79

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over