ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1125A>C (rs73215912)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000577124 SCV000789701 uncertain significance Cystic fibrosis 2017-02-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000769 SCV001157820 uncertain significance not specified 2018-08-22 criteria provided, single submitter clinical testing The CFTR c.1125A>C; p.Leu375Phe variant (rs73215912), is reported in the literature in the compound heterozygous state in multiple individuals affected with congenital bilateral absence of vas deferens (Chiang 2008, Jezequel 1996, Wu 2005), and in the heterozygous state in unaffected individuals (Berg 2013, Dorfman 2010, Palermo 2016). This variant is reported in ClinVar (Variation ID: 53196), and is found in the non-Finnish European population with an overall allele frequency of 0.01% (11/111,140 alleles) in the Genome Aggregation Database. The leucine at codon 375 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu375Phe variant is uncertain at this time. References: Berg JS et al. An informatics approach to analyzing the incidentalome. Genet Med. 2013 Jan;15(1):36-44. Chiang HS et al. CFTR mutation analysis of a Caucasian father with congenital bilateral absence of vas deferens, a Taiwanese mother, and twins resulting from ICSI procedure. J Formos Med Assoc. 2008 Sep;107(9):736-40. Dorfman R et al. Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet. 2010 May;77(5):464-73. Jezequel P et al. Identification of a novel mutation in CFTR gene exon 8 (L375F) in a CUAVD phenotype. Hum Genet. 1996 Apr;97(4):548-9. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. Wu CC et al. Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2005 Sep;20(9):2470-5.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192399 SCV001360486 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2019-08-30 criteria provided, single submitter clinical testing Variant summary: CFTR c.1125A>C (p.Leu375Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250222 control chromosomes, exclusively reported within the Non-Finnish European subpopulation with a frequency of 8.8e-05 in the gnomAD database. This frequency is not higher than the expected maximum frequency for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (8.8e-05 vs. 0.013), allowing no conclusion about variant significance. c.1125A>C has been reported in the literature in individuals affected with Congenital Unilateral- (Jezequel_2000) and Bilateral Absence of the Vas Deferens (Dork_1997, Jezequel_2000, Wu_2005). These data indicate that the variant is likely to be associated with disease. The variant has also been reported in a patient with cystic fibrosis (Faa_2006) and in an individual with chronic pancreatitis (Palermo_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000577124 SCV001425366 uncertain significance Cystic fibrosis 2020-05-08 criteria provided, single submitter clinical testing CFTR c.1125A>C has been identified in multiple individuals with congenital absence of the vas deferens. There is an entry in ClinVar for this variant. This CFTR variant (rs73215912) is rare (<0.1%) in a large population dataset (gnomAD: 10/250100 total alleles; 0.004%; no homozygotes). Three bioinformatic tools queried predict that this substitution would probably be damaging and the leucine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of c.1125C>A to be uncertain at this time.
Invitae RCV000577124 SCV001577029 likely pathogenic Cystic fibrosis 2020-10-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 375 of the CFTR protein (p.Leu375Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs73215912, ExAC 0.005%). This variant has been observed to be homozygous or in combination with another CFTR variant in individuals affected with congenital absence of vas deferens (PMID: 8834261, 9272157, 11101688), and has been shown on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (PMID: 15905293, 18796364). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 53196). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577124 SCV000678884 not provided Cystic fibrosis no assertion provided literature only
Natera, Inc. RCV000577124 SCV001465602 uncertain significance Cystic fibrosis 2020-10-20 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.