rs121908755

Positions:

• chr7-117587800-G-A
• chr7-117587800-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):​c.1646G>A​(p.Ser549Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,611,174 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,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S549R) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:24 O:1
• 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 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr7-117587799-A-C is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 38733.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 7-117587800-G-A is Pathogenic according to our data. Variant chr7-117587800-G-A is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 7116.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117587800-G-A is described in Lovd as [Pathogenic]. Variant chr7-117587800-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1646G>A	p.Ser549Asn	missense_variant	12/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1646G>A	p.Ser549Asn	missense_variant	12/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000877 AC: 22 AN: 250912 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135576

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1458870 Hom.: 0 Cov.: 28 AF XY: 0.0000413 AC XY: 30 AN XY: 725934

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74464

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000335 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:24 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2016	Variant summary: The c.1646G>A variant affects a conserved nucleotide, resulting in amino acid change from Ser to Asn. 4/5 in-silico tools predict this variant to be damaging. This variant is found in 13/120694 control chromosomes at a frequency of 0.0001077, which does not exceed maximal expected frequency of a pathogenic allele (0.0129603). This variant is a well-known pathogenic variant and has been reported in numerous CF patients. Variants affecting same amino acid, i.e. p.Ser549Arg, p.Ser549Ile, have been classified as pathogenic, suggesting Ser549 is critical for CFTR function. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 549 of the CFTR protein (p.Ser549Asn). This variant is present in population databases (rs121908755, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 1695717, 1721624, 7544319, 22658665, 23974870, 24440181, 25042876, 29360847). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1778G>A. ClinVar contains an entry for this variant (Variation ID: 7116). 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: 22293084, 23974870, 25042876). This variant disrupts the p.Ser549 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 26, 1990	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 27, 2023	This heterozygous mis-sense variant is identified in a 4 month female with fever, respiratory infection, seizures, and epileptic encephalopathy. This nucleotide change is present in gnomAD database with a low allele frequency 0.0085% [PM2]. Insilico prediction [REVEL=0.91] predicts deleterious nature of this variant [PP3]. This variant is identified in trans [PM3] with a previously reported “Pathogenic” p.Phe508del variant . A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 7116] with “Pathogenic” interpretation by multiple submitter [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic". -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 15, 2019	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000492.3(CFTR):c.1646G>A(S549N) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 1695717, 18456578, and 23974870. Classification of NM_000492.3(CFTR):c.1646G>A(S549N) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.1646G>A (p.Ser549Asn) missense variant in CFTR gene has been reported in individuals affected with cystic fibrosis, and is associated with pancreatic insufficiency (Ooi CY, Durie PR., 2015; Sharma et al., 2015). Experimental studies have shown that this variant causes defective channel gating, resulting in decreased chloride conductance (Sharma et al., 2015). This variant is reported with the allele frequency (0.008%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ser at position 549 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser549Asn in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 02, 2022	The p.S549N pathogenic mutation (also known as c.1646G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1646. The serine at codon 549 is replaced by asparagine, an amino acid with highly similar properties. This mutation was identified in a homozygous individual with an elevated sweat chloride level, growth failure, reduced lung function, and Psuedomonas aeruginosa colonization (Curtis A et al. J. Med. Genet., 1993 Feb;30:164-6). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency; in addition, a functional study found this mutation resulted in significantly decreased rates of chloride conductance compared to wild type (Sosnay PR et al. Nat Genet. 2013; 45(10):1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 03, 2020	The CFTR c.1646G>A; p.Ser549Asn variant (rs121908755) is reported in the literature as a common variant in individuals affected with cystic fibrosis, and is associated with pancreatic insufficiency (Castellani 2008, Cutting 1990, Masica 2015, Sharma 2015, Sosnay 2013). This variant is also reported in individuals affected with CFTR-related disorders when found with a pathogenic-mild variant on the opposite chromosome (Masson 2013, Ooi 2012, Sharma 2014). This variant is reported in ClinVar (Variation ID: 7116), and is found in the general population with an overall allele frequency of 0.0085% (24/282312 alleles) in the Genome Aggregation Database. The serine at codon 549 is highly conserved and is located in the ATP binding site, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate defects in channel gating and function (Sharma 2015, Yu 2012). Additionally, other variants at this codon (c.1645A>C; p.Ser549Arg, c.1647T>G; p.Ser549Arg) have been reported in individuals with cystic fibrosis and are considered pathogenic (Castellani 2008, Masica 2015, Sosnay 2013). Based on available information, the p.Ser549Asn variant is considered to be pathogenic. References: Castellani C et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96. Cutting GR et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366-9. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015 Apr 1;24(7):1908-17. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. Ooi CY and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sharma H et al. Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers. Mol Hum Reprod. 2014 Sep;20(9):827-35. Sharma H et al. Function, pharmacological correction and maturation of new Indian CFTR gene mutations. J Cyst Fibros. 2015 Jan;14(1):34-41. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. Yu H et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012 May;11(3):237-45. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 13, 2019	The variant was found in at least one symptomatic individual. The variant predicted to have a damaging effect on the protein. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant is damaging to protein function(s) relevant to disease mechanism. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 05, 2022	- -

CFTR-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 16, 2023	The CFTR c.1646G>A variant is predicted to result in the amino acid substitution p.Ser549Asn. This variant has previously been reported to be causative for cystic fibrosis (Cutting et al. 1990. PubMed ID: 1695717; Hamosh et al. 1991. PubMed ID: 1721624; Brancolini et al. 1995. PubMed ID: 7544319; Watson et al. 2004. PubMed ID: 15371902; Sosnay et al. 2013. PubMed ID: 23974870; De Boeck et al. 2014. PubMed ID: 24440181; Sharma et al. 2014. PubMed ID: 25042876; Sutanto et al. 2018. PubMed ID: 29360847). This variant was also reported in at least two patients with pancreatitis (Ooi et al. 2012. PubMed ID: 22658665). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227854-G-A). 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

-

- -

Hereditary pancreatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

Feb 22, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 27, 2024

- -

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	0.95
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.7	H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D;.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0010	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.98
MVP		1.0
MPC		0.018
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.99
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: rs121908755; hg19: chr7-117227854;