rs150691494

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000492.4(CFTR):c.902A>G(p.Tyr301Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,613,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 5.24

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13123178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.902A>G	p.Tyr301Cys	missense_variant	Exon 8 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.902A>G	p.Tyr301Cys	missense_variant	Exon 8 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000291

AC:

AN:

250950

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1461060

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00444

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000432

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Aug 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP2, PP3 -

Jun 15, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.902A>G; p.Tyr301Cys variant (rs150691494, ClinVar Variation ID: 198738) is reported in the literature in individuals with cystic fibrosis or related symptoms (El-Seedy 2016, Krenkova 2013) and in several newborns with hypertrypsinemia or a positive newborn screen but also normal sweat chloride (Castellani 1999, Ooi 2015, Scotet 2001). This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.42% (44/10364 alleles) in the Genome Aggregation Database (v2.1.1). The tyrosine at codon 301 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.86). However, given the lack of clinical and functional data, the significance of the p.Tyr301Cys variant is uncertain at this time. References: Castellani C et al. Cystic fibrosis mutations in heterozygous newborns with hypertrypsinemia and low sweat chloride. Am J Hum Genet. 1999 Jan;64(1):303-4. PMID: 9915972. El-Seedy A et al. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations in North Egyptian population: implications for the genetic diagnosis in Egypt. Cell Mol Biol (Noisy-le-grand). 2016 Nov 30;62(13):21-28. PMID: 28040058. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. PMID: 23276700. Ooi CY et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015 Jun;135(6):e1377-85. PMID: 25963003. Scotet V et al. Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis. Clin Genet. 2001 Jan;59(1):42-7. PMID: 11168024. -

Apr 19, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Y301C variant in the CFTR gene has been reported previously in individuals with an additional variant in CFTR who screened positive for cystic fibrosis on newborn screening; however, these individuals had inconclusive diagnosis with normal sweat chloride levels at followup (Castellani et al., 1999; Ooi et al., 2015). The Y301C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y301C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R297W, A299T) have been reported in the Human Gene Mutation Database in association with CFTR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y301C as a variant of uncertain significance. -

Cystic fibrosis

Uncertain:4

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y301C variant (also known as c.902A>G), located in coding exon 8 of the CFTR gene, results from an A to G substitution at nucleotide position 902. The tyrosine at codon 301 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in two newborns with an elevated immunoreactive trypsinogen (IRT) and normal sweat chloride levels, who were also heterozygous for p.F508del (Castellani C et al. Am. J. Hum. Genet., 1999 Jan;64:303-4; Ooi CY et al. Pediatrics, 2015 Jun;135:e1377-85). This variant was detected as heterozygous in a newborn with cystic fibrosis-related metabolic syndrome and in 1/177 CF and CFTR-related patients, but a second CFTR alteration was not detected in these patients (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403; Baaran AE et al. Turk J Med Sci, 2019 Dec;49:1655-1661). In another study, this variant was identified in an individual with cystic fibrosis; however, complete genotype and phenotype information was not provided (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This alteration was also identified in an individual with asthma and an individual with lung cancer (Tzetis M et al. Hum. Genet., 2001 Mar;108:216-21; Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22). This variant was also detected in 1/1279 Sicilian infertile patients who underwent CFTR screening (Chamayou S et al. BMC Med Genet, 2020 May;21:89). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 301 of the CFTR protein (p.Tyr301Cys). This variant is present in population databases (rs150691494, gnomAD 0.5%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9921909, 11303517, 11354633, 23276700, 28040058). ClinVar contains an entry for this variant (Variation ID: 198738). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CFTR-related disorder

Uncertain:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Nov 30, 2017

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Apr 05, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.902A>G (p.Tyr301Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251692 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00029 vs 0.013), allowing no conclusion about variant significance. c.902A>G has been reported in the literature in sequencing/genotyping studies, as examples, 1. with p.F508del in a neonate with raised immunoreactive trypsinogen concentration (IRT) and low sweat chloride (18 mEq/liter), 2. in a patient in low sweat chloride (<30 mmol/L) and an inconclusive diagnosis of CF (Castellani_1999, Ooi_2015), 3. as a non-informative genotype in patients with asthama (Tzetis_2001), lung cancer (Bombieri_1998), infertility (Chamayou_2020), unaffected carriers (Scotet_2001), settings of diagnostic CF genotyping (Wei_2006, Krenkova_2012, Trujillano_2015, El-Seedy_2016), 4. with other CFTR variants in patients/newborns lacking sufficient clinical evidence (Schwartz_2009, Poulou_2014, Olsowiec-Chlebna_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9921909, 9915972, 11303517, 32357917, 28040058, 23276700, 33836782, 25963003, 24784896, 19324992, 11168024, 26436105, 11354633, 16617247, 36409994). ClinVar contains an entry for this variant (Variation ID: 198738). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

May 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Jun 16, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.3

M;.;.;.;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.5

D;.;.;D;.

REVEL

Pathogenic

0.86

Sift

Benign

0.061

T;.;.;T;.

Sift4G

Uncertain

0.0030

D;.;.;D;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.95

MVP

0.99

MPC

0.0052

ClinPred

0.12

GERP RS

5.4

Varity_R

0.38

gMVP

0.91

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