chr7-117590357-G-C

Position:

chr7-117590357-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The ENST00000003084.11(CFTR):c.1684G>C(p.Val562Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000761 in 1,602,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V562I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 7.38

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1684G>C	p.Val562Leu	missense_variant	13/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1684G>C	p.Val562Leu	missense_variant	13/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250340

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000618

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000765

AC:

111

AN:

1450404

Hom.:

Cov.:

AF XY:

0.0000763

AC XY:

AN XY:

721284

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000158

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:

0.0000852

Gnomad4 OTH exome

AF:

0.000168

GnomAD4 genome

AF:

0.0000724

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00000600

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 562 of the CFTR protein (p.Val562Leu). This variant is present in population databases (rs1800097, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 8956039, 24586523, 28544683). This variant is also known as c.1816G>C. ClinVar contains an entry for this variant (Variation ID: 53341). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 13, 2022	The p.V562L variant (also known as c.1684G>C), located in coding exon 13 of the CFTR gene, results from a G to C substitution at nucleotide position 1684. The valine at codon 562 is replaced by leucine, an amino acid with highly similar properties. This alteration was first reported in a 9 year old male with mild cystic fibrosis (CF) and pancreatic sufficiency; he was also heterozygous for a known pathogenic mutation, however phase (cis vs. trans) was not confirmed (Hughes DJ, et al. Hum. Mutat. 1996; 8:340-7). Three additional individuals with clinical diagnoses of CF were determined to be heterozygous for this variant, however a second mutation was not identified (Zitkiewicz E, et al. PLoS ONE 2014 Mar;9(2):e89094; Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206) In addition, this alteration has been detected in conjunction with the 5T variant (phase confirmed trans in one case) in two individuals with CF features (Aalbers BL et al. J. Cyst. Fibros., 2019 Jul; Casals T, et al. Clin. Genet. 2004; 65:490-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 30, 2020	This variant has been reported in individuals presenting with mild cystic fibrosis (CF) and related symptoms. CFTR c.1684G>C is located within nucleotide-binding domain 1, however, it is outside of the important Walker A and Walker B regions. This variant (rs1800097) is rare (<0.1%) in a large population dataset6 (gnomAD: 15/281690 total alleles; 0.005%; no homozygotes) and has been reported in ClinVar. An alternate missense variant (p.Val562Ile) at this residue has been reported as not CF-causing when combined with another CF-causing variant. Of three bioinformatics tools queried, two predict that p.Val562Leu would be tolerated, while one predicts that it would be damaging. The valine residue at this position is highly evolutionarily conserved across most species assessed. We consider the clinical significance of c.1684G>C to be uncertain at this time. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2024	Variant summary: CFTR c.1684G>C (p.Val562Leu) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250722 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (5.2e-05 vs 0.013), allowing no conclusion about variant significance. c.1684G>C has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Hughes_996b, Zietkiewicz_2013, Pavone_2010, Soltysova_2017, Aalbers_2020, Raraigh_2022) or bronchiectasis (Casals_2004) without strong evidence for causality. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31331863, 26990548, 10746558, 15151509, 8956039, 33836782, 20651897, 34782259, 28544683, 24586523). ClinVar contains an entry for this variant (Variation ID: 53341). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 27, 2018	Notes: reported as compound het with 5T in one individual with bronchiectisis; a single het in an individual with CF; and possibly as a double het in an individ ual with CF. Computation predictions are mixed. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 09, 2017	The CFTR c.1684G>C, p.Val562Leu variant (rs1800097) has been reported in an individual with mild cystic fibrosis and pancreatic sufficiency, and found in-trans with p.Ile507del (Hughes 1996). It is listed in ClinVar (Variation ID: 53341), and observed in the Genome Aggregation Database general population database at a frequency of 0.005 percent (14/276196 alleles). The valine at residue 562 is highly conserved, but computational algorithms (Align GVGD: C25; Mutation Taster: disease causing; PolyPhen-2: benign; SIFT: damaging) are inconclusive on the variant's impact on the protein. Due to the limited information regarding this variant, its clinical significance could not be determined with certainty. References: Hughes D et al. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes. Hum Mutat. 1996; 8(4):340-7. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with cystic fibrosis or CFTR-related disorders without confirmation of a pathogenic variant on the opposite allele (in trans), as well as in healthy individuals (Pallares-Ruiz 1999, Casals 2004, Modiano 2005, Zietkiewicz 2014, Soltysova 2017); This variant is associated with the following publications: (PMID: 24586523, 10601093, 31331863, 28544683, 10746558, 16251901, 15151509, 8956039, 15536480) -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 01, 2018

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;D;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.077

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.66

D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

-0.59

N;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.1

N;.;N;.

REVEL

Pathogenic

0.68

Sift

Benign

0.033

D;.;D;.

Sift4G

Benign

0.24

T;.;T;.

Polyphen

0.054

B;.;.;.

Vest4

0.93

MutPred

0.91

Loss of phosphorylation at Y563 (P = 0.1225);.;.;.;

MVP

0.99

MPC

0.0041

ClinPred

0.13

GERP RS

3.9

Varity_R

0.81

gMVP

0.92

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