rs397508542

Positions:

chr7-117611763-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000492.4(CFTR):c.3322G>C(p.Val1108Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000484 in 1,613,080 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O:1

Conservation

PhyloP100: 5.71

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a transmembrane_region Helical; Name=11 (size 20) in uniprot entity CFTR_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3322G>C	p.Val1108Leu	missense_variant	20/27	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.3322G>C	p.Val1108Leu	missense_variant	20/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+4466C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151788

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250936

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135630

show subpopulations

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461292

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726952

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:

0.0000666

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151788

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74120

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:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 02, 2022	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1108 of the CFTR protein (p.Val1108Leu). This variant is present in population databases (rs397508542, gnomAD 0.004%). This missense change has been observed in individual(s) with a CFTR-related disorder and congenital absence of the vas deferens (PMID: 17413420, 28603918). ClinVar contains an entry for this variant (Variation ID: 53719). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Genome-Nilou Lab	Sep 05, 2021	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 08, 2024	The p.V1108L variant (also known as c.3322G>C), located in coding exon 20 of the CFTR gene, results from a G to C substitution at nucleotide position 3322. The valine at codon 1108 is replaced by leucine, an amino acid with highly similar properties. This alteration was reported in a 37 year old with CBAVD and no other clinical manifestations of cystic fibrosis; he was also heterozygous for the 11-5T variant, phase not reported (Grangeia A, Genet. Med. 2007 Mar; 9(3):163-72). This amino acid position is well 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 16, 2022

Variant summary: CFTR c.3322G>C (p.Val1108Leu) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250936 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3322G>C has been reported in the literature as a non-informative genotype (second allele not-specified) or in cis with a pathogenic CFTR allele (see detailed below) in individuals with features of CBAVD, chronic bronchitis (COPDGene study cohort) (example, Grangeia_2007, Steiner_2011, Pagin_2016, Safareli_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At-least one co-occurrence in cis with another pathogenic variant(s) have been reported (CFTR c.3454G>C, p.Asp1152His) reportedly in trans with the 5T allele in an individual with CBAVD, providing supporting evidence for a benign role (Steiner_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 18, 2020

The CFTR c.3322G>C; p.Val1108Leu variant (rs397508542) is reported in the literature in an individual affected with congenital absence of the vas deferens who also carried a pathogenic-mild CFTR variant (Grangeia 2007). This variant is reported in ClinVar (Variation ID: 53719), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 1108 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Val1108Leu variant is uncertain at this time. References: Grangeia A et al. Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. Genet Med. 2007;9(3):163-172. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;T;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.2

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.2

N;.;.;N;.

REVEL

Pathogenic

0.76

Sift

Benign

0.047

D;.;.;D;.

Sift4G

Uncertain

0.0020

D;.;.;D;.

Polyphen

0.98

D;.;.;.;.

Vest4

0.86

MutPred

0.88

Loss of helix (P = 0.0376);.;.;.;.;

MVP

1.0

MPC

0.0044

ClinPred

0.54

GERP RS

5.4

Varity_R

0.86

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

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