rs397508531

Positions:

• chr7-117611733-T-C
• chr7-117611733-T-G

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.3292T>C​(p.Trp1098Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1098C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 7.93

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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 chr7-117611735-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 53709.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 7-117611733-T-C is Pathogenic according to our data. Variant chr7-117611733-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 53707.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117611733-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3292T>C	p.Trp1098Arg	missense_variant	20/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3292T>C	p.Trp1098Arg	missense_variant	20/27	1	NM_000492.4	P2
	ENST00000456270.1	n.177+4496A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727024

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2023	The p.W1098R pathogenic mutation (also known as c.3292T>C and 3424T>C), located in coding exon 20 of the CFTR gene, results from a T to C substitution at nucleotide position 3292. The tryptophan at codon 1098 is replaced by arginine, an amino acid with dissimilar properties. This mutation was described in an individuals with cystic fibrosis (CF) who presented with recurrent chest infections and mild pancreatic insufficiency (Zielenski J et al, Hum. Mutat. 1995 ; 5(1):43-7). By in vitro studies, this alteration was shown to cause impaired CFTR protein processing/glycosylation as well as reduced cAMP-activated anion channel activity (Seibert FS et al, J. Biol. Chem. 1996 Jun; 271(25):15139-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Another alteration at the same codon, p.W1098C (c.3294G>C), has been detected in an individual with pancreatic sufficient CF (Orozco L et al, Hum. Genet. 2000 Mar; 106(3):360-5). Based on the available evidence, p.W1098R is classified as a pathogenic mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2023	Variant summary: CFTR c.3292T>C (p.Trp1098Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 251088 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3292T>C has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Zielenski_1995, Shackelton_1994). These data suggest the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Seibert_1996), finding that the variant disrupts biosynthetic processing leading to retention in the endoplasmic reticulum and also severely disrupts channel activity. The following publications have been ascertained in the context of this evaluation (PMID: 7515303, 7537150, 8662892). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jul 03, 2015	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Jan 07, 2021	Criteria Codes: PM2 PP3 PS3_VStr PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 07, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 11, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 18, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp1098 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 7537150, 10798368, 18178635), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1098 of the CFTR protein (p.Trp1098Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7537150). ClinVar contains an entry for this variant (Variation ID: 53707). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 24, 2018

Not found in the total gnomAD dataset, and the data is high quality (0/282434 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-11	D;.;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.99
MutPred		0.96		Loss of catalytic residue at L1096 (P = 0.0026);.;.;.;.;
MVP		1.0
MPC		0.012
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
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: rs397508531; hg19: chr7-117251787;