7-117611638-G-T

Variant names:

• chr7-117611638-G-T
• rs121909019
• NM_000492.4:c.3197G>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.3197G>T​(p.Arg1066Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1066C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.94

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 18 ACMG points.

• PM1: In a helix (size 6) 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117611637-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-117611638-G-T is Pathogenic according to our data. Variant chr7-117611638-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3197G>T	p.Arg1066Leu	missense_variant	Exon 20 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3197G>T	p.Arg1066Leu	missense_variant	Exon 20 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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: PM2_SUP, PM3, PM5_STR, PP3, PP4 -

Dec 06, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3197G>T (p.Arg1066Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250888 control chromosomes (gnomAD). c.3197G>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Mercier_1993, Kilinc_2002, Kolesar_2008, Hosseini Nami_2023). These data indicate that the variant is likely to be associated with disease. Other variants affecting the same codon have been classified as pathogenic by our lab (c.3196C>T/p.Arg1066Cys, c.3197G>A/p.Arg1006His), supporting the critical relevance of codon 1066 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 0.5% 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: 7683628, 12439892, 37274793, 38388235, 19202204). ClinVar contains an entry for this variant (Variation ID: 53678). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.8	D;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.99
MutPred		0.96		Loss of MoRF binding (P = 0.0424);.;.;.;.;
MVP		0.99
MPC		0.015
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.99

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: rs121909019; hg19: chr7-117251692;