ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2249C>T (p.Pro750Leu) (rs140455771)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078984 SCV000110852 uncertain significance not provided 2017-11-07 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078984 SCV000281655 likely pathogenic not provided 2014-11-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282290 SCV000603030 uncertain significance Hereditary pancreatitis 2020-09-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855589 SCV000696892 uncertain significance not specified 2021-03-23 criteria provided, single submitter clinical testing 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 higher than expected 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 (Li_2012) and CF (Prontera_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant has approximately 49% of wild-type activity as assessed in-vitro (Raraigh_2018). 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. Nine other ClinVar submitters (evaluation after 2014) cited the variant as pathogenic/likely pathogenic (n=5) and uncertain significance (n=4). Based on the evidence outlined above,the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000675059 SCV000800517 uncertain significance Cystic fibrosis 2017-04-19 criteria provided, single submitter clinical testing
Mendelics RCV000675059 SCV000886150 likely pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000675059 SCV000915207 likely pathogenic Cystic fibrosis 2018-11-30 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078984 SCV001134126 uncertain significance not provided 2019-12-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004472 SCV001163517 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009488 SCV001169583 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001014920 SCV001175693 likely pathogenic Inborn genetic diseases 2020-09-16 criteria provided, single submitter clinical testing 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 mutation was first described in a individual with cystic fibrosis who was compound heterozygous for p.F508del on the other chromosome, and 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). In another study, an infant with a positive newborn screening result was found to carry this alteration and p.F508del (phase unknown); this individual developed respiratory symptoms but no gastrointestinal problems and was pancreatic sufficient (Calvin J et al. Arch. Dis. Child., 2012 Dec;97:1043-7). 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). Functional analysis of this variant in CFBE cells demonstrated 48% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;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 Accessed January 2, 2018). 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 the majority of available evidence to date, this variant is likely to be pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000675059 SCV001371793 likely pathogenic Cystic fibrosis 2020-01-07 criteria provided, single submitter clinical testing CFTR variant associated with variable clinical consequences. See for phenotype information.
Mayo Clinic Laboratories, Mayo Clinic RCV000078984 SCV001714844 uncertain significance not provided 2020-03-13 criteria provided, single submitter clinical testing
GeneDx RCV000078984 SCV001774273 uncertain significance not provided 2021-06-02 criteria provided, single submitter clinical testing Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); Published functional studies are inconclusive: decreased chloride conductance compared to wild type, but higher function than was seen for pathogenic variants associated with full expressivity (Raraigh et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29805046, 16189704, 30698611, 30833958, 27535533, 28830496, 23076339, 28992757, 20706124, 17481968, 22103471, 20846557, 27728908, 10798368, 21416780, 16963320, 28712885, 12007216, 14998948, 22483971, 25087612, 17272608, 26199320, 16423550, 17432547)
Nilou-Genome Lab RCV000675059 SCV001822099 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001588874 SCV001822100 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-22 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000078984 SCV001551337 uncertain significance not provided no assertion criteria provided clinical testing 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.

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