Submissions for variant NM_000492.4(CFTR):c.200C>T (p.Pro67Leu)

gnomAD frequency: 0.00004  dbSNP: rs368505753

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056357	SCV000071515	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV000660821	SCV000783060	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056357	SCV000074533	pathogenic	Cystic fibrosis	2024-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 67 of the CFTR protein (p.Pro67Leu). This variant is present in population databases (rs368505753, gnomAD 0.006%). This missense change has been observed in individual(s) with cystic fibrosis (CF), congenital bilateral absence of vas deferens, or other CFTR-related conditions (PMID: 9507391, 16840743, 22658665, 23974870). 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: 53425). 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). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000056357	SCV000220721	likely pathogenic	Cystic fibrosis	2014-09-24	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000724153	SCV000331669	pathogenic	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056357	SCV000696882	pathogenic	Cystic fibrosis	2016-07-29	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.200C>T (p.Pro67Leu) variant involves the alteration of a conserved nucleotide and is present in ABC transporter type 1, transmembrane domain of the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121266 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous CF-affected individuals in the literature, particularly in patients with non-classic CF with consistent recessive genotypes, and has been shown to display a mean chloride conductance <10% compared to wildtype (Sosnay_2013, Kraus_2007). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724153	SCV000888075	pathogenic	not provided	2022-06-08	criteria provided, single submitter	clinical testing	In the published literature, the variant has been associated with mild CF signs and symptoms with compound heterozygous individuals often being pancreatic sufficient, have abnormal sweat chloride levels, and are responsive to therapeutics (PMID: 6840743 (1983), 23974870 (2013), 25732475 (2015), 28392015 (2017)). The variant has been reported to be common in the Scottish population (PMID: 9507391 (1998)). Functional studies have shown that this variant has a damaging effect on CFTR maturation and function (PMID: 23974870 (2013), 23891399 (2014), 27660821 (2016), 33781744 (2021)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV001004231	SCV001163107	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000056357	SCV001167250	pathogenic	Cystic fibrosis	2019-10-16	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information.
CFTR-France	RCV000056357	SCV001169420	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000724153	SCV001714824	pathogenic	not provided	2024-07-26	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000056357	SCV001984854	pathogenic	Cystic fibrosis	2020-05-27	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in many individuals affected with cystic fibrosis (CF), congenital bilateral absence of vas deferens, or other CFTR-related conditions (PMID: 9507391, 22658665, 23974870, 16840743). Individuals with this variant and a second pathogenic allele are typically found to have lower sweat chloride levels than the average CF (http://cftr2.org/mutation/scientific/P67L/). Experimental studies have shown that this missense change affects the chloride conduction function in vitro (PMID:23974870, 23891399). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/282408) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.200C>T (p.Pro67Leu) variant on protein function. Based on the available evidence, the c.200C>T (p.Pro67Leu) variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000724153	SCV002019257	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000724153	SCV002051745	likely pathogenic	not provided	2021-02-02	criteria provided, single submitter	clinical testing	PS3, PP2, PM3_Supporting, PM2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000056357	SCV002507400	pathogenic	Cystic fibrosis	2021-07-05	criteria provided, single submitter	clinical testing
Mendelics	RCV002247433	SCV002518664	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056357	SCV002720940	pathogenic	Cystic fibrosis	2024-12-03	criteria provided, single submitter	clinical testing	The p.P67L pathogenic mutation (also known as c.200C>T), located in coding exon 3 of the CFTR gene, results from a C to T substitution at nucleotide position 200. The proline at codon 67 is replaced by leucine, an amino acid with similar properties. This mutation has been described in a Scottish cohort of individuals with a mild phenotype, including in trans with p.G542* in an 18-year-old male with recurrent chest infections and pancreatic insufficiency as well as in trans with p.F508del in a 1-year-old female with a probable diagnosis of cystic fibrosis (CF) and an initial abnormal sweat chloride level followed by two equivocal sweat chloride tests (Gilfillan A et al. J. Med. Genet., 1998 Feb;35:122-5). In vitro functional studies showed that while CFTR transcripts with this pathogenic mutation had similar mRNA levels compared to wildtype, the amount of processed mature protein was significantly decreased (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). This mutation is associated with borderline sweat chloride levels and pancreatic sufficiency (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.
Fulgent Genetics, Fulgent Genetics	RCV002496711	SCV002813236	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-05-23	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001826628	SCV004046297	pathogenic	CFTR-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in multiple individuals with cystic fibrosis (CF) and other CFTR-related disorders (PMID: 9507391, 22658665, 23974870, 16840743). The c.200C>T (p.Pro67Leu) variant is present in the CFTR2 website as a CF disease-causing variant when combined with another CF-causing variant (http://cftr2.org/mutation/scientific/P67L/). In-vitro functional studies showed that this alteration affects the channel function (PMID:23974870, 23891399). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/282408) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.200C>T (p.Pro67Leu) variant on protein function. Based on the available evidence, the c.200C>T (p.Pro67Leu) variant is classified as Pathogenic.
Baylor Genetics	RCV003473472	SCV004211633	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724153	SCV004562666	pathogenic	not provided	2023-10-02	criteria provided, single submitter	clinical testing	The CFTR c.200C>T; p.Pro67Leu variant (rs368505753), is reported in the literature in multiple individuals in the compound heterozygous state affected with cystic fibrosis (Gilfillan 1998, Kingsmore 2021, Raraigh 2022, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 53425) and is observed on ten alleles in the Genome Aggregation Database, indicating it is not a common polymorphism and. In vitro/In vivo functional analyses demonstrate altered CFTR protein folding, reduced mature CTFR protein, and reduced chloride transport (Sabusap 2021, Van Goor 2014). The proline at codon 67 is highly conserved and computational analyses predict that this variant is deleterious (REVEL:0.926). Based on available information, this variant is considered to be pathogenic. References: Gilfillan A, et al. P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population. J Med Genet. 1998. PMID: 9507391 Kingsmore SF, et al. A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. 2021. Am J Hum Genet. PMID: 36007526. Raraigh KS, et al. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022. PMID: 34782259. Sabusap CM, et al. The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue. 2021. J Biol Chem. PMID: 33781744. Sosnay PR, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013. 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. PMID: 23891399.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724153	SCV001744286	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724153	SCV001956860	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826628	SCV002080087	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826628	SCV002507484	pathogenic	CFTR-related disorder	2021-07-05	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826628	SCV004757311	pathogenic	CFTR-related disorder	2024-01-01	no assertion criteria provided	clinical testing	The CFTR c.200C>T variant is predicted to result in the amino acid substitution p.Pro67Leu. This variant has been reported to be causative for cystic fibrosis (https://cftr2.org, Sosnay et al. 2013. PubMed ID: 23974870; Claustres et al. 1993. PubMed ID: 7691344). In summary, we classify this variant as pathogenic.