7-117652877-C-G
Variant summary
Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP2PP3PP5_Very_Strong
The NM_000492.4(CFTR):c.3909C>G(p.Asn1303Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,598,060 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. N1303H) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Publications
- cystic fibrosisInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
- congenital bilateral absence of vas deferensInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary chronic pancreatitisInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 14 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | MANE Select | c.3909C>G | p.Asn1303Lys | missense | Exon 24 of 27 | NP_000483.3 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | TSL:1 MANE Select | c.3909C>G | p.Asn1303Lys | missense | Exon 24 of 27 | ENSP00000003084.6 | ||
| CFTR | ENST00000699602.1 | c.3903C>G | p.Asn1301Lys | missense | Exon 24 of 27 | ENSP00000514471.1 | |||
| CFTR | ENST00000426809.5 | TSL:5 | c.3819C>G | p.Asn1273Lys | missense | Exon 23 of 26 | ENSP00000389119.1 |
Frequencies
GnomAD3 genomes 0.000158 AC: 24AN: 152068Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000144 AC: 36AN: 249546 AF XY: 0.000171 show subpopulations
GnomAD4 exome AF: 0.000158 AC: 228AN: 1445874Hom.: 0 Cov.: 27 AF XY: 0.000179 AC XY: 129AN XY: 720082 show subpopulations
Age Distribution
GnomAD4 genome 0.000158 AC: 24AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74420 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:20Uncertain:1Other:2
The CFTR c.3909C>G (p.Asn1303Lys) missense variant is a well-known, widely reported pathogenic variant that accounts for approximately 1.3% of disease alleles, and is often associated with a classic cystic fibrosis (CF) phenotype (Ong et al. 2001). The Cystic Fibrosis Mutation Database (http://www.genet.sickkids.on.ca/cftr/Home.html) indicates that the p.Asn1303Lys variant is the fourth most common CFTR variant worldwide, and the Clinical and Functional Translation of CFTR (CFTR2) database (http://cftr2.org) reports the p.Asn1303Lys variant in over 2100 patients, noting that it is a cystic fibrosis-causing variant. Across a selection of the available literature, the p.Asn1303Lys variant has also been reported in five patients with congenital bilateral absence of the vas deferens (CBAVD), including three compound heterozygotes and two heterozygotes in whom a second variant was not identified (Steiner et al. 2011; Tomaiuolo et al. 2011), and in four patients with chronic pancreatitis, including three compound heterozygotes and one heterozygote (Steiner et al. 2011; Hamoir et al. 2013). The p.Asn1303Lys variant is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Asn1303Lys variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Variant interpretted as pathogenic and reported on 03/20/2016 by GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
ACMG criteria used to clasify this variant: PS3, PS4, PP3, PP1
Criteria applied: PM3_VSTR,PS3,PM5_STR,PM2_SUP,PP3,PP4
The p.N1303K pathogenic mutation (also known as c.3909C>G), located in coding exon 24 of the CFTR gene, results from a C to G substitution at nucleotide position 3909. The asparagine at codon 1303 is replaced by lysine, an amino acid with similar properties. In one study, this mutation was identified in 216 cystic fibrosis alleles, including 10 homozygous individuals with elevated sweat chloride levels and decreased lung function. Of the 6 homozygous individuals with reported pancreatic status, all were pancreatic insufficient (Osborne L et al. Hum. Genet., 1992 Aug;89:653-8). In vitro functional studies determined that this mutation prevents the maturation, trafficking, and subsequent activity of the CFTR protein (Gregory RJ et al. Mol. Cell. Biol., 1991 Aug;11:3886-93). This pathogenic mutation is associated with elevated sweat chloride levels, decreased lung function, and pancreatic insufficiency; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
This mutation has been previously reported as disease-causing and was found once in our laboratory in a homozygous state in a 13-year-old male with a clinical diagnosis of cystic fibrosis. Heterozygotes are expected to be asymptomatic carriers.
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1303 of the CFTR protein (p.Asn1303Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with CFTR-related disorders, including cystic fibrosis, congenital bilateral absence of the vas deferens, and chronic pancreatitis (PMID: 1380943, 12767731, 15371902, 21520337, 22658665, 23951356, 23974870). ClinVar contains an entry for this variant (Variation ID: 7136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23891399, 23974870, 25799511). For these reasons, this variant has been classified as Pathogenic.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.016%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.83 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.91 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007136 /PMID: 1998343). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 32220772). Different missense changes at the same codon (p.Asn1303His, p.Asn1303Ile, p.Asn1303Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007218, VCV000053846, VCV001685264 /PMID: 1284537). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PS3,PM3(strong),PP3,PM2,PM5
not provided Pathogenic:15
The CFTR c.3909C>G; p.Asn1303Lys variant (rs80034486), is reported in the literature in multiple individuals diagnosed with cystic fibrosis, often associated with pancreatic insufficiency (Osborne 1991, Osborne 1992, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7136), and is found in the general population with an overall allele frequency of 0.014% (34/244424 alleles) in the Genome Aggregation Database. The asparagine at codon 1303 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.83). Functional characterization of the variant protein indicates a defect in CFTR processing, resulting in a severe reduction in chloride transport activity (Sosnay 2013, Van Goor 2014). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. PMID: 22658665 Osborne L et al. A mutation in the second nucleotide binding fold of the cystic fibrosis gene. Am J Hum Genet. 1991 48(3):608-12. PMID: 1998343 Osborne L et al. Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene. Hum Genet. 1992 89(6):653-8. PMID: 1380943 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. PMID: 23974870 Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36. PMID: 23891399
The N1303K variant in the CFTR gene has been reported previously as a CF-causing variant in patients with abnormal sweat chloride levels, pancreatic insufficiency, and mild to moderate lung disease (Sosnay et al., 2013; Osborne et al, 1991). The N1303K variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N1303K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the ABC transporter 2 domain that is conserved across species. Cell lines expressing the N1303K CFTR variant show loss of baseline chloride transport compared to those expressing wild type protein (Van Goor et al., 2014). A missense variant at the same residue, N1303H, was reported in a patient with severe pulmonary disease and pancreatic insufficiency (Claustres et al., 1992). We interpret N1303K as a pathogenic variant.
DNA sequence analysis of the CFTR gene demonstrated a sequence change, c.3909C>G, in exon 24 that results in an amino acid change, p.Asn1303Lys. The p.Asn1303Lys change affects a highly conserved amino acid residue located in a domain of the CFTR protein that is known to be functional. The p.Asn1303Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in several individuals with CFTR-related disorders including cystic fibrosis, congenital bilateral absence of the vas deferens, and chronic pancreatitis (PMID: 23951356, 23974870, 21520337, 9014613). Functional studies have shown that this sequence change has an impact on CFTR protein maturation and abolishes ion channel function (PMID: 23974870, 23891399, 25799511). It is one of the most commonly reported pathogenic variant (PMID: 11232455, 1380943, 12767731, 15371902, 22658665). This sequence change has been described in the gnomAD database with a frequency of 0.018% in the European subpopulation (dbSNP rs80034486). These collective evidences indicate that this sequence change is pathogenic.
The frequency of this variant in the general population, 0.00018 (23/128054 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in the homozygous state and with other CF variants in trans to be particularly associated with a pancreatic insufficient phenotype, however, variable lung function phenotypes from unusually mild to severe have been observed (PMID: 1380943 (1992), 23974870 (2013), and 26208274 (2015)). Functional analysis has described this variant as Class II causing defective protein processing, protein degradation, insignificant levels of mature CFTR, and conductance (PMID: 1712898 (1991), 23891399 (2014), 25799511 (2015), 26823392 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
CFTR-related disorder Pathogenic:3
The CFTR c.3909C>G variant is predicted to result in the amino acid substitution p.Asn1303Lys. This variant has been reported to be causative for cystic fibrosis (Sosnay et al. 2013. PubMed ID: 23974870; Masson et al. 2013. PubMed ID: 23951356; Osborne et al. 1991. PubMed ID: 1998343; Watson et al. 2004. PubMed ID: 15371902). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.
Spermatogenic failure, Y-linked, 2 Pathogenic:1
ACMG categories: PS3,PS4,PP3,PP5
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Hereditary pancreatitis Pathogenic:1
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
Cystic fibrosis diagnostic test Pathogenic:1
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at