ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.200C>T (p.Pro67Leu) (rs368505753)

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Total submissions: 7
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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
Counsyl RCV000056357 SCV000220721 likely pathogenic Cystic fibrosis 2014-09-24 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724153 SCV000331669 pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000056357 SCV000074533 pathogenic Cystic fibrosis 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 67 of the CFTR protein (p.Pro67Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs368505753, ExAC 0.006%). This variant has been reported 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 patient (~61mEq/L vs 96mEq/L) and often have pancreatic sufficiency (http://cftr2.org/mutation/scientific/P67L/), suggesting that this missense is a milder allele. ClinVar contains an entry for this variant (Variation ID: 53425). Experimental studies have shown that this missense change impairs chloride conduction function in vitro (PMID: 23974870, 23891399). For these reasons, this variant has been classified as Pathogenic.
PharmGKB RCV000660821 SCV000783060 drug response ivacaftor response - Efficacy 2018-03-22 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000724153 SCV000888075 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing

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