rs75549581

chr7-117587829-G-Achr7-117587829-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):c.1675G>A(p.Ala559Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,576,110 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. A559P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 8.82

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 Pathogenic. Variant got 18 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, 13 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 chr7-117587829-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2573429.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 7-117587829-G-A is Pathogenic according to our data. Variant chr7-117587829-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7123.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117587829-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1675G>A	p.Ala559Thr	missense_variant	12/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1675G>A	p.Ala559Thr	missense_variant	12/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250586 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135406

Gnomad AFR exome AF: 0.000247

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: 0.0000162 AC: 23 AN: 1423968 Hom.: 0 Cov.: 24 AF XY: 0.0000141 AC XY: 10 AN XY: 710940

Gnomad4 AFR exome AF: 0.000552

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: 0.0000677

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

Gnomad4 AFR AF: 0.000217

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000421 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:8

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 26, 1990	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2016	Variant summary: The CFTR c.1675G>A (p.Ala559Thr) variant involves the alteration of a conserved nucleotide. Variant is located in the ABC transporter-like domain, P-loop containing nucleoside triphosphate hydrolase domain, and the AAA+ATP domain in the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120302 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in many affected individuals worldwide and multiple functional studies showed that variant lead to sever defect in CFTR processing and lead to non-detectable level of chloride transport. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	NM_000492.3(CFTR):c.1675G>A(A559T) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870, 18456578 and 1695717. Classification of NM_000492.3(CFTR):c.1675G>A(A559T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2022	The p.A559T pathogenic mutation (also known as c.1675G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1675. The alanine at codon 559 is replaced by threonine, an amino acid with similar properties. In one study, this mutation was detected in the homozygous state in an individual with poor feeding, cough, sudden weight loss, pancreatic insufficiency, and elevated sweat chloride levels; the individual's parents were confirmed carriers (McDowell T et al. Am. J. Hum. Genet., 1995 Sep;57:734). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition, in vitro functional studies showed reduced mature CFTR protein levels as well as undetectable chloride conductance (Gregory RJ et al. Mol. Cell. Biol., 1991 Aug;11:3886-93; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on available evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 559 of the CFTR protein (p.Ala559Thr). This variant is present in population databases (rs75549581, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1695717, 7668304, 9150159, 9950364, 12007216, 18456578, 23670503, 23974870, 25489051). 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: 7123). 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: 1712898, 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2017	The A559T variant in the CFTR gene has been reported previously in individuals with cystic fibrosis (Cutting et al., 1990; Keyeux et al., 2003). It is reported as pathogenic in ClinVar but additional evidence is not available (SCV000071496.3, SCV000225523.3, SCV000331552.2, SCV000485203.1; Landrum et al., 2016). Functional studies indicate that cells expressing the A599T variant have a low level of mature CFTR and do not have chloride transport ability (Van Goor et al., 2014). The A559T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A559T 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 across species. Missense variants in nearby residues (including L558S, R560K, R560T, R560S, A561E, V562I, V562L) have been reported in the Human Gene Mutation Database in association with cystic fibrosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A559T as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 12, 2016	- -

CFTR-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 05, 2024	The CFTR c.1675G>A variant is predicted to result in the amino acid substitution p.Ala559Thr. This variant has been reported to be causative for cystic fibrosis (referred to as G1807>A in Cutting et al. 1990. PubMed ID: 1695717; Sosnay et al. 2013. PubMed ID: 23974870; www.CFTR2.org). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

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

Apr 14, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D;.;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0090	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.98
MVP		1.0
MPC		0.016
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.97

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: rs75549581; hg19: chr7-117227883;