rs121908802

Positions:

chr7-117535263-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.595C>T(p.His199Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,962 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H199Q) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 7.52

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 18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr7-117535264-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 54019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 7-117535263-C-T is Pathogenic according to our data. Variant chr7-117535263-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54018.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535263-C-T 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.595C>T	p.His199Tyr	missense_variant	6/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.595C>T	p.His199Tyr	missense_variant	6/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

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:

0.0000116

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:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 199 of the CFTR protein (p.His199Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 7525450, 10798368, 12007216, 15858154, 18456578, 27143075, 28608624). ClinVar contains an entry for this variant (Variation ID: 54018). 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: 23974870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 07, 2022	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2023	The p.H199Y pathogenic mutation (also known as c.595C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 595. The histidine at codon 199 is replaced by tyrosine, an amino acid with similar properties. This mutation was reported in multiple individuals with cystic fibrosis and a second mutation in trans; in vitro studies using HeLa cells expressing this mutation showed a severe processing defect of the CFTR protein (Sosnay PR et al, Nat. Genet. 2013 Oct; 45(10):1160-7). In addition, a disease-causing alteration, p.H199R, has been described in the same codon (D'Apice MR et al, BMC Med. Genet. 2004 Apr; 5:8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2017	Variant summary: The CFTR c.595C>T (p.His199Tyr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the ABC transporter type 1, transmembrane domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/121410 control chromosomes). The variant has been identified in numerous cystic fibrosis patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 30, 2016	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 19, 2017

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

2.9

M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.4

D;.;.;D;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0060

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MutPred

0.92

Gain of catalytic residue at H199 (P = 0.0198);Gain of catalytic residue at H199 (P = 0.0198);Gain of catalytic residue at H199 (P = 0.0198);.;Gain of catalytic residue at H199 (P = 0.0198);

MVP

1.0

MPC

0.0099

ClinPred

1.0

GERP RS

5.5

Varity_R

0.92

gMVP

0.96

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