rs193922504

Positions:

chr7-117587827-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.1673T>C(p.Leu558Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000126 in 1,583,114 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L558L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 7.05

Variant links:

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]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 7-117587827-T-C is Pathogenic according to our data. Variant chr7-117587827-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 35829.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117587827-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1673T>C	p.Leu558Ser	missense_variant	12/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1673T>C	p.Leu558Ser	missense_variant	12/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250672

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430928

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 03, 2019	The p.L558S pathogenic mutation (also known as c.1673T>C and 1805T>C), located in coding exon 12 of the CFTR gene, results from a T to C substitution at nucleotide position 1673. The leucine at codon 558 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in cystic fibrosis patients from Mexico, France, Italy, Spain, Latin America, and the Czech Republic (Orozco L, Hum. Genet. 2000 Mar; 106(3):360-5; Duguépéroux I, Eur. Respir. J. 2005 Mar; 25(3):468-73; Castaldo G, Ann. Hum. Genet. 2005 Jan; 69(Pt 1):15-24; Alonso MJ, Ann. Hum. Genet. 2007 Mar; 71(Pt 2):194-201; Pérez MM, J. Cyst. Fibros. 2007 May; 6(3):194-208; Kenková P, J. Cyst. Fibros. 2013 Sep; 12(5):532-7). In one study, functional assays demonstrated significantly reduced CFTR activity equal to 1.2% of wild-type levels (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Based on the available evidence, p.L558S is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 21, 2022	Variant summary: CFTR c.1673T>C (p.Leu558Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) and AAA+ ATPase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251088 control chromosomes. c.1673T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Cystic Fibrosis (example, Kuwertz-Broking_1995, Dell Edera_2014, Dugueperoux_2005, Sosnay_2013, Kammesheidt_2006, Lucarelli_2013, Sanchez_2016). 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 a significant reduction in CFTR maturation, though chloride conduction study was not performed (Sosnay_2013). Multiple clinical diagnostic laboratories, the CFTR-2 database and the CFTR-France database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 07, 2021	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 558 of the CFTR protein (p.Leu558Ser). This variant is present in population databases (rs193922504, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital bilateral absence of vas deferens and/or cystic fibrosis (PMID: 7525450, 9401110, 9439669, 10798368, 15638824, 22483971, 25910067). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35829). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Aug 31, 2018	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 12, 2019

The CFTR c.1673T>C; p.Leu558Ser variant (rs193922504) is reported in the literature in multiple patients with cystic fibrosis (Chavez-Saldana 2010, Sosnay 2013, CFTR2 database), or CBAVD when found with a mild CFTR pathogenic variant (Li 2012). Functional analyses of the variant protein show a significant decrease in function (Raraigh 2018, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 35829), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 558 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010 62(6):546-52. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 11(4):316-23. 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. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.5

D;.;D;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.99

MutPred

0.92

Gain of disorder (P = 0.0054);.;.;.;

MVP

1.0

MPC

0.015

ClinPred

1.0

GERP RS

5.3

Varity_R

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over