7-117590409-A-G

Position:

• chr7-117590409-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Strong

The NM_000492.4(CFTR):​c.1736A>G​(p.Asp579Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,918 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 drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D579Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: drug response reviewed by expert panel P:12 O:2
• Conservation: PhyloP100: 8.64

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 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr7-117590408-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1705994.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-117590409-A-G is Pathogenic according to our data. Variant chr7-117590409-A-G is described in ClinVar as [drug_response]. Clinvar id is 53365.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=10, not_provided=1, drug_response=1}. Variant chr7-117590409-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1736A>G	p.Asp579Gly	missense_variant	13/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1736A>G	p.Asp579Gly	missense_variant	13/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250214 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135414

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450918 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721670

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: drug response

Submissions summary: Pathogenic:12 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2019	Variant summary: CFTR c.1736A>G (p.Asp579Gly) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 250214 control chromosomes (gnomAD). c.1736A>G has been reported in the literature in compound heterozygous state with another pathogenic variant or in homozygous state in multiple individuals affected with Non-classic Cystic Fibrosis (e.g. Al-Atawi_2015, Brancolini_1995, Picci_1998, Salvatore_2004, Sofia_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to cause a considerable decrease in chloride conductance and transport (Sosnay_2013, Van Goor_2014). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 15, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 579 of the CFTR protein (p.Asp579Gly). This variant is present in population databases (rs397508288, gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7544319, 15463898, 26494713, 27738188, 27812499). ClinVar contains an entry for this variant (Variation ID: 53365). 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 have shown that this missense change affects CFTR function (PMID: 23891399). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2020	The p.D579G pathogenic mutation (also known as c.1736A>G), located in coding exon 13 of the CFTR gene, results from an A to G substitution at nucleotide position 1736. The aspartic acid at codon 579 is replaced by glycine, an amino acid with similar properties. This mutation has been observed in the homozygous state in patients with non-classical cystic fibrosis presentations, including borderline or intermediate sweat chloride levels, mild or no pulmonary disease, and pancreatic sufficiency (Picci L et al. Hum. Mutat. 1999; 13:173; Salvatore D et al. J. Cyst. Fibros. 2004; 3:135-6; Al-Atawi MS et al. BMJ Case Rep, 2015 Oct;2015:). The p.D579G alteration has been reported as a variant of varying clinical consequences (VVCC) and has been identified in trans with a pathogenic mutation in individuals with no disease, CFTR-related disorders, or with cystic fibrosis (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Bombieri C et al. Semin Respir Crit Care Med, 2015 Apr;36:180-93; Terlizzi V et al. J. Med. Genet., 2017 04;54:224-235). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 18, 2019	- -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 28, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 18, 2019	- -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jul 03, 2015

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

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

GeneDx

Nov 02, 2022

Published functional studies demonstrate a damaging effect: reduced chloride transport (Sosnay et al., 2013; VanGoor et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); Also known as CFTR c.1868A>G; This variant is associated with the following publications: (PMID: 15463898, 23974870, 25489051, 22658665, 29805046, 16132229, 26823392, 25910067, 26494713, 22423042, 25583415, 23891399, 10094564, 27812499, 31036917, 7544319, 27738188, 31130284) -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 29, 2023

- -

ivacaftor response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.3	D;.;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0050	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		1.0
MutPred		0.98		Gain of catalytic residue at V580 (P = 0.0645);.;.;.;
MVP		1.0
MPC		0.012
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.99
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 0
DS_DL_spliceai		0.27		Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397508288; hg19: chr7-117230463;