rs397508272

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-117509038-T-C
• chr7-117509038-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.169T>C​(p.Trp57Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,446,526 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W57G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117509038-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 7-117509038-T-C is Pathogenic according to our data. Variant chr7-117509038-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53346.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.169T>C	p.Trp57Arg	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>C	p.Trp57Arg	missense_variant	Exon 3 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446526 Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3 AN XY: 720792

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: 0.0000944

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Other:1

Apr 10, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W57R variant (also known as c.169T>C), located in coding exon 3 of the CFTR gene, results from a T to C substitution at nucleotide position 169. The tryptophan at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in conjunction with a pathogenic mutation in CFTR by our laboratory; however, the phase (whether in cis or trans) is not known. This alteration has also been identified in multiple individuals diagnosed with cystic fibrosis (Kinnunen S et al. J. Cyst. Fibros., 2005 Dec;4:233-7; De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142; Auzenbaha M et al. Diagnostics (Basel), 2022 Nov;12:). Based on internal structural analysis, this alteration is more disruptive than known pathogenic variants nearby (Liu F et al. Cell, 2017 Mar;169:85-95.e8). Furthermore, an in vitro study showed that this tryptophan residue is essential for processing of the CFTR protein (Cormet-Boyaka E et al. Proc. Natl. Acad. Sci. U.S.A., 2004 May;101:8221-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.169T>C (p.Trp57Arg) 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 250754 control chromosomes. c.169T>C has been reported in the literature in individuals affected with Cystic Fibrosis (Duursma_2022, VanBiervliet_2018, Raraigh_2022, Sickkids_database). In addition another missense variant altering this amino acid (p.Trp57Gly) has been classified as pathogenic in ClinVar, supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jan 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs397508272). This sequence change replaces tryptophan with arginine at codon 57 of the CFTR protein (p.Trp57Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 28830496, 16051530, Invitae). ClinVar contains an entry for this variant (Variation ID: 53346). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Trp57 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7544319, 29805046). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jun 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.169T>C (p.Trp57Arg) variant has been reported in the published literature in individuals with cystic fibrosis (PMIDs: 36428953 (2022), 34782259 (2022), 28830496 (2017), 16051530 (2005)) and CFTR-related hepatic disorder (PMID: 35697137 (2022)). A functional study indicates that disruption of the p.Trp57 residue results in a significant loss of properly-processed CFTR protein (PMID: 15141088 (2004)), and consistent with this finding, a different missense at this codon (p.Trp57Gly) was shown to have deleterious effects on CFTR function (PMID: 29805046 (2018)). The frequency of the c.169T>C (p.Trp57Arg) variant in the general population, 0.000064 (2/31402 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Oct 10, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

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	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;H
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.3	D;.;.;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Uncertain	0.0020	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.97
MutPred		0.88		Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);
MVP		1.0
MPC		0.012
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.98

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: rs397508272; hg19: chr7-117149092;