NM_000492.4:c.169T>G

Variant names:

• chr7-117509038-T-G
• rs397508272
• NM_000492.4:c.169T>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.169T>G​(p.Trp57Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 17) in uniprot entity CFTR_HUMAN there are 5 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, 0.979
• PP5: Variant 7-117509038-T-G is Pathogenic according to our data. Variant chr7-117509038-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 53347.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117509038-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.169T>G	p.Trp57Gly	missense_variant	Exon 3 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.169T>G	p.Trp57Gly	missense_variant	Exon 3 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:6 Other:1

Mar 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 57 of the CFTR protein (p.Trp57Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7544319, 23974870). ClinVar contains an entry for this variant (Variation ID: 53347). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). This variant disrupts the p.Trp57 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

May 09, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W57G pathogenic mutation (also known as c.169T>G), located in coding exon 3 of the CFTR gene, results from a T to G substitution at nucleotide position 169. The tryptophan at codon 57 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation (referred to as 301T>G) was described in a patient with cystic fibrosis (CF) who had a second pathogenic mutation on the other allele (Brancolini V et al. Hum. Genet., 1995 Sep;96:312-8). It was also reportedly detected on two CF alleles in a Czech cohort (Kenkov&aacute; P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this mutation is more disruptive than known pathogenic variants nearby (Liu F et al. Cell, 2017 Mar;169:85-95.e8). In addition, in vitro studies showed that this tryptophan residue is essential for processing of the CFTR protein and W57G has almost no CFTR function (Cormet-Boyaka E et al. Proc. Natl. Acad. Sci. U.S.A., 2004 May;101:8221-6; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed <May 9, 2018>). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Mar 26, 2020

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 02, 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.169T>G (p.Trp57Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.169T>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. McCague_2019, Brancolini_1995). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 0.75% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 7544319, 30888834). ClinVar contains an entry for this variant (Variation ID: 53347). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 08, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

CFTR-related disorder Pathogenic:1

Jan 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.169T>G variant is predicted to result in the amino acid substitution p.Trp57Gly. This variant has been reported in the compound heterozygous state in multiple individuals with cystic fibrosis (Table 2, Brancolini et al. 1995. PubMed ID: 7544319; Table 1, Křenková et al. 2013. PubMed ID: 23276700; Table S4, Raraigh et al. 2022. PubMed ID: 34782259; CFTR2 database, cftr2.org; CFTR-France database, https://cftr.iurc.montp.inserm.fr/cftr). Multiple in vitro studies have demonstrated that this variant disrupts CFTR protein processing and trafficking to the cell membrane, leading to a complete loss of chloride channel function (Raraigh et al. 2018. PubMed ID: 29805046; Sabusap et al. 2021. PubMed ID: 33781744; Ramalho et al. 2022. PubMed ID: 35008443). This variant has not been reported in a large population database, indicating this variant is rare. A different missense variant at the same amino acid (p.Trp57Arg) has also been reported in individuals with cystic fibrosis (Table 1, Kinnunen et al. 2005. PubMed ID: 16051530; Table 2, De Wachter et al. 2017. PubMed ID: 28830496; Table 1, Auzenbaha et al. 2022. PubMed ID: 36428953). Taken together, the p.Trp57Gly variant is interpreted as pathogenic. -

not provided Pathogenic:1

Sep 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.169T>G; p.Trp57Gly variant (rs397508272) is reported in the literature in several individuals affected with cystic fibrosis (Brancolini 1995; Raraigh 2018). Functional analyses of the variant protein show it has a deleterious effect on protein folding, maturation, and function (Sabusap 2021). This variant is reported as pathogenic by an expert panel in ClinVar (Variation ID: 53347) and is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The tryptophan at codon 57 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.834). Based on available information, this variant is considered to be pathogenic. References: Brancolini V et al. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995 Sep;96(3):312-8. PMID: 7544319. 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. PMID: 29805046. Sabusap CM et al. The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue. J Biol Chem. 2021. Jan-Jun;296:100598. PMID: 33781744. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Jun 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.92	D;.;.;D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;H
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.9	D;.;.;D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D;.;.;D;.
Sift4G	Benign	0.071	T;.;.;T;.
Polyphen		0.13	B;.;.;.;.
Vest4		0.97
MutPred		0.88		Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);
MVP		0.97
MPC		0.012
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs397508272; hg19: chr7-117149092;