rs397508310

chr7-117591993-A-Gchr7-117591993-A-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.1826A>G(p.His609Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,595,240 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. H609L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 8.60

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr7-117591992-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1691298.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 7-117591993-A-G is Pathogenic according to our data. Variant chr7-117591993-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 53398.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117591993-A-G is described in Lovd as [Pathogenic]. Variant chr7-117591993-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1826A>G	p.His609Arg	missense_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1826A>G	p.His609Arg	missense_variant	14/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 6.93e-7 AC: 1 AN: 1443022 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000253

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: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2017	Variant summary: The CFTR c.1826A>G (p.His609Arg) variant located in the P-loop containing nucleoside triphosphate hydrolase (via InterPro) causes a missense change involving a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 119096 control chromosomes. Multiple publications cite the variant in affected individuals diagnosed with CF including both compound heterozygotes and 4 homozygous individuals, who are indicated to have a more severe phenotype than the compound heterozygous individuals. Although, no clinical diagnostic laboratories have cited this variant with a classification. In addition, LCA has classified additional missense variants surrounding the variant of interest in the pathogenic spectrum such as c.1837A>G (p.Ala613Thr VUS-possibly pathogenic), c.1841A>G (p.Asp614Gly pathogenic), and c.1853T>C (p.Ile618Thr VUS-possibly pathogenic), therefore, suggesting this region could be important for proper CFTR function. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 2023	The p.H609R pathogenic mutation (also known as c.1826A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 1826. The histidine at codon 609 is replaced by arginine, an amino acid with highly similar properties. This mutation was initially reported as identified in one Italian cystic fibrosis (CF) chromosome; however, complete genotype and phenotype information was not provided (Padoan R et al. Acta Paediatr., 2002;91:82-7). This mutation was identified in the homozygous state in 4 individuals with CF from 3 Ecuadorian families; all 4 individuals has elevated sweat chloride levels and the parents in each family were confirmed carriers of this mutation. Three of these individuals had Pseudomonas colonization and reduced lung function; two of these individuals were pancreatic insufficient while the third was pancreatic insufficient. The fourth individual in this study was an infant and these analyses were not performed (Moya-Quiles MR et al. J. Cyst. Fibros., 2009 Jul;8:280-1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 609 of the CFTR protein (p.His609Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital bilateral absence of the vas deferens and cystic fibrosis (PMID: 14685937, 16189704, 16963320, 19457724, 26708955). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53398). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CFTR: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 15, 2020	Not found in the total gnomAD dataset, and the data is high quality. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 29, 2018

The CFTR c.1826A>G; p.His609Arg variant (rs397508310) has been reported in numerous individuals affected with cystic fibrosis, either in the homozygous state or in trans with another pathogenic variant (Keyeux 2003, McGinniss 2005, Moya-Quiles 2009, Ortiz 2017, Schrijver 2016, CFTR2 database). The variant is listed in ClinVar (Variation ID: 53398) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The histidine at residue 609 is moderately conserved, and computational algorithms (PolyPhen-2: damaging; SIFT: tolerated) predict conflicting effects of this variant on protein structure/function. Using a cell-based assay measuring CFTR-generated current, one study observed p.His609Arg variant activity at 2.2% of wildtype (Rareigh 2018). Based on available information, this variant is considered to be likely pathogenic. References: CFTR2 database: https://cftr2.org Keyeux G et al. CFTR mutations in patients from Colombia: implications for local and regional molecular diagnosis programs. Hum Mutat. 2003 Sep;22(3):259. McGinniss MJ et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005 Dec;118(3-4):331-8. Moya-Quiles MR et al. CFTR H609R mutation in Ecuadorian patients with cystic fibrosis. J Cyst Fibros. 2009 Jul;8(4):280-1. Ortiz SC et al. Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation. Mol Genet Genomic Med. 2017 Nov;5(6):751-757. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50. -

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

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Mar 09, 2018

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.3	L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D;.;D;.
REVEL	Pathogenic	0.81
Sift	Benign	0.17	T;.;T;.
Sift4G	Uncertain	0.0080	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.93
MutPred		0.92		Gain of MoRF binding (P = 0.017);.;.;.;
MVP		0.99
MPC		0.0059
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397508310; hg19: chr7-117232047;