NM_000492.4(CFTR):c.169T>C (p.Trp57Arg) AND Cystic fibrosis

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Jun 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000577294.13

Allele description [Variation Report for NM_000492.4(CFTR):c.169T>C (p.Trp57Arg)]

NM_000492.4(CFTR):c.169T>C (p.Trp57Arg)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC113664106:CFTR intron 2 DNase I hypersensitive site [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.169T>C (p.Trp57Arg)

HGVS:

NC_000007.14:g.117509038T>C
NG_016465.4:g.48255T>C
NG_062452.1:g.676T>C
NM_000492.4:c.169T>CMANE SELECT
NP_000483.3:p.Trp57Arg
NP_000483.3:p.Trp57Arg
LRG_663t1:c.169T>C
LRG_663:g.48255T>C
LRG_663p1:p.Trp57Arg
NC_000007.13:g.117149092T>C
NM_000492.3:c.169T>C

Protein change:

W57R

Links:

dbSNP: rs397508272

NCBI 1000 Genomes Browser:

rs397508272

Molecular consequence:

NM_000492.4:c.169T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000679333	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001490645	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 27, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7544319, 29805046, 28830496, 16051530, 28492532
SCV001821985	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004000028	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 10, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15141088, 16051530, 28830496, 36428953 Citation Link,
SCV004020645	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34782259, 35697137, 30144894 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations.

Brancolini V, Cremonesi L, Belloni E, Pappalardo E, Bordoni R, Seia M, Russo S, Padoan R, Giunta A, Ferrari M.

Hum Genet. 1995 Sep;96(3):312-8.

PubMed [citation]

PMID:: 7544319

Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.

Raraigh KS, Han ST, Davis E, Evans TA, Pellicore MJ, McCague AF, Joynt AT, Lu Z, Atalar M, Sharma N, Sheridan MB, Sosnay PR, Cutting GR.

Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. doi: 10.1016/j.ajhg.2018.04.003. Epub 2018 May 24.

PubMed [citation]

PMID:: 29805046
PMCID:: PMC5992123

See all PubMed Citations (11)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001490645.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. 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. 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 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). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001821985.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV004000028.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020645.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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