rs367850319

chr7-117534321-C-Achr7-117534321-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000492.4(CFTR):c.535C>A(p.Gln179Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000156 in 1,605,674 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q179Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 O:1
• Conservation: PhyloP100: 7.17

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.535C>A	p.Gln179Lys	missense_variant	5/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.535C>A	p.Gln179Lys	missense_variant	5/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152084 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250702 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1453590 Hom.: 0 Cov.: 26 AF XY: 0.0000166 AC XY: 12 AN XY: 723736

Gnomad4 AFR exome AF: 0.0000301

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: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:5 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2022	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 179 of the CFTR protein (p.Gln179Lys). This variant is present in population databases (rs367850319, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 11668613). ClinVar contains an entry for this variant (Variation ID: 53993). 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 not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 19491324, 23666117). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 23, 2022	CFTR c.535C>A has been identified in multiple individuals with elevated sweat chloride concentration and features of cystic fibrosis who also have a second CFTR variant, although the phase of these variants is not known. This variant (rs367850319) is rare (<0.1%) in a large population dataset (gnomAD: 4/250702 total alleles; 0.0016%; no homozygotes) and has been reported in ClinVar (Variation ID: 53993). BayPR, an algorithm that uses population data to assign disease liability to variants, predicts that this variant is unlikely to be CF-causing. A single in vitro functional study suggests that this variant is associated with a decrease in CFTR function, but this decrease is not to the level observed with other CF-causing variants in this study. This functional data has not been replicated to our knowledge. The glutamine at this position is evolutionarily conserved across all species assessed. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of CFTR c.535C>A to be uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 2021	The p.Q179K variant (also known as c.535C>A), located in coding exon 5 of the CFTR gene, results from a C to A substitution at nucleotide position 535. The glutamine at codon 179 is replaced by lysine, an amino acid with similar properties. This variant was observed with another pathogenic CFTR alteration in a Hispanic patient who had elevated sweat chloride level, pulmonary symptoms, and pancreatic insufficiency (Wong LJ et al. Hum. Mutat., 2001 Oct;18:296-307). In vitro studies have demonstrated that the variant results in reduced CFTR maturation and function (Caputo A et al. J. Pharmacol. Exp. Ther., 2009 Sep;330:783-91; Okiyoneda T et al. Nat Chem Biol, 2013 Jul;9:444-54). However, it remains unknown if the observed reduction is sufficient to cause disease. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 14, 2017	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2019	The CFTR c.535C>A; p.Gln179Lys variant (rs367850319) is reported in the literature in individuals affected with cystic fibrosis (CF) or CFTR-related disorders, however, a second variant was not identified in these individuals (Casals 2004, Keiles 2006, Schrijver 2005, Wong 2004). One individual with CF was reported to carry a second pathogenic CFTR variant, but the phase of the two variants was not determined (Wong 2001). This variant is reported in ClinVar (Variation ID: 53993), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamine at codon 179 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate a maturation defect but partial protein function (Caputo 2009). Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Caputo A et al. Mutation-specific potency and efficacy of cystic fibrosis transmembrane conductance regulator chloride channel potentiators. J Pharmacol Exp Ther. 2009 Sep;330(3):783-91. Casals T et al. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? Clin Genet. 2004 Jun;65(6):490-5. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 May;7(2):289-99. Wong LJ et al. Improved detection of CFTR mutations in Southern California Hispanic CF patients. Hum Mutat. 2001 Oct;18(4):296-307. Wong LJ and Alper OM. Detection of CFTR mutations using temporal temperature gradient gel electrophoresis. Electrophoresis. 2004 Aug;25(15):2593-601. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	Reported previously with a second variant in a patient with cystic fibrosis including pancreatic insufficiency (Wong et al., 2001); Also reported as heterozygous with no second variant identified in patients with pancreatitis or bronchiectasis (Giefer et al., 2017; Casals et al., 2004); Although published functional studies showed reduced maturation, iodide transport measured in COS-7 cells were inconsistent with this variant being a CF-causing mutation (Caputo et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18556774, 16049310, 15151509, 28502372, 11668613, 15300780, 19491324, 25087612, 15858154) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 26, 2023

Variant summary: CFTR c.535C>A (p.Gln179Lys) results in a 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 1.6e-05 in 250702 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.535C>A has been reported in the literature in patients with CF (n=2) as well as CFTR-related phenotypes such as pancreatitis (n=1) and bronchiectasis (n=1) without strong evidence for or against pathogenicity (e.g. Wong_2001, Casals_2004, Keiles_2006, Schrijver_2005). In one CF patient, it was reported in compound heterozygosity with another truncating variant; however, it is not specified whether such zygosity was confirmed by parental testing (Wong_2001/Sickkids db). It has also been reported in the compound heterozygous state together with F508del in an individual who was CF screen-positive with an inconclusive diagnosis as an infant, yet who did not receive a change in diagnosis during a follow-up period of approximately 7 years (Gonska_2021). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significantly reduced maturation and iodide transport measured in COS-7 cells at levels not consistent with that for a CF-causing mutation (Caputo_2009, Okiyoneda_2013). The following publications have been ascertained in the context of this evaluation (PMID: 34740355, 19491324, 15151509, 34814176, 17003641, 23666117, 16049310, 15858154, 18556774, 15300780, 11668613). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 19, 2019

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.020	D;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		0.85	P;.;.;.
Vest4		0.91
MVP		0.99
MPC		0.0037
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.88
gMVP		0.93

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: rs367850319; hg19: chr7-117174375;