rs140455771
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_000492.4(CFTR):c.2249C>T(p.Pro750Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,613,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.2249C>T | p.Pro750Leu | missense_variant | Exon 14 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000381 AC: 58AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000288 AC: 72AN: 249946Hom.: 0 AF XY: 0.000281 AC XY: 38AN XY: 135142
GnomAD4 exome AF: 0.000627 AC: 916AN: 1460760Hom.: 1 Cov.: 32 AF XY: 0.000607 AC XY: 441AN XY: 726662
GnomAD4 genome 0.000381 AC: 58AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74478
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:10Uncertain:2
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Variant summary: CFTR c.2249C>T (p.Pro750Leu) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 252642 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00029 vs 0.013), allowing no conclusion about variant significance. c.2249C>T has been reported in the literature in multiple individuals affected with CFTR-Related Disease phenotypes, ranging from asymptomatic to severe CF, and including CFTR-related disorders such as CBAVD, chronic pancreatitis, and azoospermia. Orozco et al (2000) reported a patient with a severe CF phenotype and early onset of the disease who also carried the common CF-associated p.Phe508del mutation on the other chromosome. However, due to the methods utilized for variant detection in this study, the possibility of an undetected pathogenic variant in cis with c.2249C>T cannot be excluded. Another study reported the variant in trans with p.Phe508del in two sisters with minimal respiratory symptoms and normal growth parameters and laboratory testing results after clinical follow up for several years (Bernat_2017). c.2249C>T has been detected in additional patients carrying other pathogenic variants in trans with phenotypes of CBAVD (e.g. Li_2012 and Zou_2022) and CF (Prontera_2016). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence indicating the variant has an impact on protein function (e.g. Raraigh_2018, Bihler_2024). The most pronounced variant effect results in approximately 20% of normal chloride channel conductance relative to wild type (Bihler_2024). The CFTR2 database reports that this variant has varying consequences and that some patients with this variant and another CF-causing variant have CF while others do not. Because the clinical manifestations of CF can vary over the course of a person's lifetime, clinical correlation and follow-up are recommended. The following publications have been ascertained in the context of this evaluation (PMID: 12007216, 21416780, 14998948, 28830496, 17272608, 22483971, 30698611, 30888834, 16189704, 26199320, 10798368, 28801929, 27728908, 29805046, 34996830, 31674704, 31672438, 19014821, 17481968, 20846557, 35109852, 29216686, 38388235). ClinVar contains an entry for this variant (Variation ID: 53460). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information. -
The p.P750L variant (also known as c.2249C>T), located in coding exon 14 of the CFTR gene, results from a C to T substitution at nucleotide position 2249. The proline at codon 750 is replaced by leucine, an amino acid with similar properties. This variant was first described in an individual with cystic fibrosis who was compound heterozygous for p.F508del on the other chromosome; the individual presented at 2 months of age with chronic lung disease and elevated sweat chloride levels (Orozco L et al. Hum Genet, 2000 Mar;106:360-5). The variant has been reported in conjunction with a CFTR pathogenic mutation in additional individuals with cystic fibrosis, as well as mildly symptomatic individuals (McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8; Calvin J et al. Arch. Dis. Child., 2012 Dec;97:1043-7, Prontera P et al. Public Health Genomics, 2016 Oct;19:336-341; De Wachter E et al. Orphanet J Rare Dis, 2017 08;12:142). This alteration has also been identified in males with congenital bilateral absence of the vas deferens (CBAVD) (Danziger KL et al. Hum. Reprod., 2004 Mar;19:540-6; Li H et al. J. Cyst. Fibros., 2012 Jul;11:316-23). However, this variant has been detected in conjunction with a pathogenic finding in this same gene in multiple individuals with no reported features of cystic fibrosis or CFTR-related disorder (Ambry internal data). Functional analysis of this variant in CFBE cells demonstrated 48% activity compared to wild type (Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077). The p.P750L alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed October 12, 2021). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic. -
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This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 750 of the CFTR protein (p.Pro750Leu). This variant is present in population databases (rs140455771, gnomAD 0.05%). This missense change has been observed in individual(s) with CFTR-related disease, congenital absence of the vas deferens, or cystic fibrosis (PMID: 10798368, 22483971, 23076339, 27728908, 28830496; internal data). 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: 53460). 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 not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 29805046). For these reasons, this variant has been classified as Pathogenic. -
This variant was classified based on the report of 1 patient with a clinically confirmed diagnosis of cystic fibrosis in the context of re-classifying variants in the German Cystic Fibrosis Registry (Muko e.V.). Patients have not been seen personally, but only reports were evaluated. Criteria applied:PS3, PM3 -
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The CFTR c.2249C>T (p.Pro750Leu) missense variant has been reported in three studies and in a total of three patients with CFTR-related disorders, all in a compound heterozygous state (Orozco et al. 2000; Storm et al. 2007; Li et al. 2012). Phenotypes included cystic fibrosis including pancreatic insufficiency, classic CF, and congenital absence of the vas deferens and the variant on the second allele was p.Phe508del in at least two of the patients. Control data are unavailable for this variant, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Pro750Leu variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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This sequence variant is a single nucleotide substitution (C>T) at position 2249 of the coding sequence of the CFTR gene that results in a proline to leucine amino acid change at residue 750 of the CF transmembrane conductance regulator protein. This residue falls in the regulator domain of the protein (UniProt). This is a previously reported variant (ClinVar 53460) that has been observed in individuals affected by cystic fibrosis (PMID: 10798368, 17481968), congenital absence of vas deferens (PMID: 35109852, 14998948, 22483971, 23076339), and other CFTR-related phenotypes (PMID: 16189704, 20846557, 27728908). Additionally, it was found as compound heterozygous with the p.Phe508del allele in two sisters that were essentially free of CFTR-related phenotypes, suggesting that this allele may not be related to disease or have low penetrance (Bernat 2017, Journal of Pulmonary Medicine and Respiratory Research). This variant is present in 130 of 402128 alleles (0.0323%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this proline to leucine amino acid change would be neutral, and the Pro750 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant indicate that it reduces activity to about 50% of wild-type protein (PMID: 29805046, 30888834). Based upon the evidence, we consider this variant to be likely pathogenic, though it may be an allele with low penetrance. ACMG Criteria: PM2, PM3, PS3, PS4 -
not provided Pathogenic:4Uncertain:3
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The CFTR p.Pro750Leu variant was identified in dbSNP (ID: rs140455771), ClinVar (reported as uncertain significance (4x) and likely pathogenic (1x)), Clinvitae, MutDB and LOVD 3.0 databases, but was not found in Cosmic. The variant was identified in control databases in 80 of 281354 chromosomes at a frequency of 0.000284 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 74 of 128492 chromosomes (freq: 0.000576), East Asian in 3 of 19916 chromosomes (freq: 0.000151) and African in 3 of 24932 chromosomes (freq: 0.00012),but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), Other, and South Asian populations. This variant has been reported in the compound heterozygous state in patients with Cystic Fibrosis (CF), including an Italian patient with CF that also carried the well-known p.F508del variant (Orozco_2000_PMID: 10798368; Prontera_2016_PMID: 27728908). However, the p.P750L variant was also identified in trans with the p.F508del variant in two sisters with normal sweat chloride testing, minimal respiratory symptoms and normal growth parameters, suggesting that this variant may not be a causal recessive variant for CF (Bernat_2017). The p.Pro750 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
The CFTR c.2249C>T (p.Pro750Leu) variant has been reported along with other CF variants in the published literature in individuals with cystic fibrosis (PMID: 10798368 (2000), 16189704 (2005), 19014821 (2008), 23076339 (2012), 27728908 (2016), 28830496 (2017)). This variant has also been reported in individuals with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 14998948 (2004), 22483971 (2012), 35109852 (2022)). Published functional study showed that the variant results in 48.6% of the wild type CFTR activity (PMID: 29805046 (2018)). The frequency of this variant in the general population, 0.00085 (43/50526 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic. -
Published functional studies are inconclusive: decreased chloride conductance and protein expression compared to wild type, but higher function than was seen for pathogenic variants associated with full expressivity (PMID: 29805046, 38388235); 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); This variant is associated with the following publications: (PMID: 25087612, 26199320, 14998948, 27728908, 16423550, 17432547, 12007216, 28712885, 16963320, 21416780, 10798368, 20846557, 22103471, 17481968, 20706124, 23076339, 30833958, 30698611, 16189704, 22483971, 34996830, 35451201, 34506673, 33946859, 35109852, 37895316, 37628659, 34782259, 36253274, 28830496, 38388235, 38515211, 28992757, 17272608, 29805046, 39062716, 39553608) -
CFTR: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
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CFTR-related disorder Pathogenic:4
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The CFTR c.2249C>T variant is predicted to result in the amino acid substitution p.Pro750Leu. This variant has been reported along with a second pathogenic variant in multiple patients with cystic fibrosis (CF) or CFTR-related disorders, including at least one patient with congenital bilateral absence of vas deferens (CBAVD) (Orozco et al. 2000. PubMed ID: 10798368; Li et al. 2012. PubMed ID: 22483971; Storm et al. 2007. PubMed ID: 17481968; McGinniss et al. 2005. PubMed ID: 16189704; Calvin et al. 2012. PubMed ID: 23076339; Prontera et al. 2016. PubMed ID: 27728908; De Wachter et al. 2017. PubMed ID: 28830496). In vitro functional studies indicated that this variant had ~49% of wild-type CFTR function (Raraigh et al. 2018. PubMed ID: 29805046). Additionally, patients with this variant combined with another CF-causing variant showed a sweat chloride measurement of 49 mEq/L (n=13), which is less than what is typically found in patients with CF (https://cftr2.org/mutation/general/P750L/). However, at least one patient has been reported with elevated and normal sweat chloride levels at different timepoints (Calvin et al. 2012. PubMed ID: 23076339). This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, these data indicate this variant causes CF with variable expressivity when in trans to a second pathogenic variant. This variant is interpreted as likely pathogenic. -
The p.Pro750Leu variant has been reported in the literature in multiple individuals with CFTR-related disease with highly variable disease presentations and severity. The p.Pro750Leu variant has been reported in trans (compound heterozygous) with the common p.Phe508del variant in an individual with a severe, early onset, Cystic Fibrosis (CF) phenotype (PMID 10798368). However, the p.Pro750Leu/p.Phe508del genotype has also been reported in some individuals with moderate or mild symptoms (Bernat 2017; PMID: 23076339). In addition, the p.Pro750Leu variant has been reported in trans with other CF-causing pathogenic variants in individuals with congenital bilateral absence of vas deferens (CBAVD) (PMID: 22483971, 35109852), and mild CF-related disease (PMID: 16189704). The p.Pro750Leu variant was reported alone with no second CF-causing variant in an individual with multiple indeterminate sweat chloride tests, chronic constipation, and poor weight gain in early childhood, who later developed chronic productive cough, sinusitis, mild bronchiectasis, lung function decline, and positive respiratory cultures for classic microorganisms of CF (PMID: 30698611). Functional testing has demonstrated the p.Pro750Leu variant protein exhibits approximately 48.6% of wildtype chloride channel activity (PMID: 29805046). The c.2249C>T (p.Pro750Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (80/281354), and is absent in the homozygous state. The c.2249C>T (p.Pro750Leu) variant affects a moderately conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Based on available information, the c.2249C>T (p.Pro750Leu) variant is classified as Likely Pathogenic with varying clinical consequences. -
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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:1Uncertain:1
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The CFTR c.2249C>T; p.Pro750Leu variant (rs140455771) has been reported in individuals with cystic fibrosis (CF), either with or without pancreatic insufficiency (De Wachter 2017, Orozco 2000, SickKids CFTR database, CFTR2 database). In trans to CF-causing pathogenic variants, the p.Pro750Leu variant has also been reported in individuals with congenital bilateral absence of vas deferens (Li 2012) and in individuals exhibiting borderline sweat chloride levels as part of a complex variant with p.Arg352Trp (McGinnis 2005, Soultan 2008). However, the p.Pro750Leu variant has also been found in trans to p.Phe508del in two sisters without significant lung or pancreatic symptoms (Bernat 2017). The p.Pro750Leu variant is listed in ClinVar (Variation ID: 53460) and is observed in the general population with an allele frequency of 0.028% (80/281354 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.655). Functional assays demonstrate the p.Pro750Leu variant protein exhibits 48.6% of wildtype chloride channel activity (Raraigh 2018). Based on available information, this variant is considered to be likely pathogenic with varying clinical consequences. References: CFTR2 database: https://cftr2.org SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1103 Bernat JA et al. Compound Heterozygosity for CFTR phe508del/Pro750Leu in Two Siblings with Normal Sweat Chloride, Lung Function, Growth, and Fecal Elastase. J Pulm Med Respir Res 2017 Jun 8;3:010. De Wachter E et al. What can the CF registry tell us about rare CFTR-mutations? A Belgian study. Orphanet J Rare Dis. 2017 Aug 22;12(1):142. PMID: 28830496. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012; 11(4):316-23. PMID: 22483971. McGinniss M et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005; 118(3-4):331-8. PMID: 16189704. Orozco L et al. Spectrum of CFTR mutations in Mexican cystic fibrosis patients: identification of five novel mutations (W1098C, 846delT, P750L, 4160insGGGG and 297-1G-->A). Hum Genet. 2000; 106(3):360-5. PMID: 10798368. 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. PMID: 29805046. Soultan Z et al. Sweat chloride testing in infants identified as heterozygote carriers by newborn screening. J Pediatr. 2008; 153(6):857-9. PMID: 19014821. -
Hereditary pancreatitis Pathogenic:1
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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at