Submissions for variant NM_000492.4(CFTR):c.94C>A (p.Leu32Met)

gnomAD frequency: 0.00001  dbSNP: rs776797377

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000598321	SCV000709400	uncertain significance	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000670047	SCV000794858	uncertain significance	Cystic fibrosis	2017-10-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000598321	SCV000883578	uncertain significance	not provided	2017-12-28	criteria provided, single submitter	clinical testing	The CFTR c.94C>A; p.Leu32Met variant (rs776797377) has been reported once in the literature in a 2 year old diagnosed with CF who also carried the pathogenic F508del variant (Prach 2013); however, phase of the two variants was not determined and large deletions and duplications were not ruled out. A different alteration at this codon (p.Leu32Pro) has also been reported once in a CF patient who also carried a pathogenic nonsense variant (Liu 2015), but the clinical significance of the p.Leu32Pro variant has not been established. The p.Leu32Met variant is observed in the general population with an overall allele frequency of 0.0008% (2/245708 alleles) in the Genome Aggregation Database. The leucine at codon 32 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. However, given the limited clinical and functional data regarding p.Leu32Met, its significance is uncertain at this time. REFERENCES Liu Y et al. Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. Respirology. 2015 Feb;20(2):312-8. Prach L et al. Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. J Mol Diagn. 2013 Sep;15(5):710-22.
Genome-Nilou Lab	RCV000670047	SCV002027326	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670047	SCV002240942	pathogenic	Cystic fibrosis	2023-03-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu32 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25580864; www.genet.sickkids.on.ca). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. ClinVar contains an entry for this variant (Variation ID: 502597). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 23810505, 27214204). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs776797377, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 32 of the CFTR protein (p.Leu32Met).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525980	SCV005040431	uncertain significance	not specified	2024-03-04	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.94C>A (p.Leu32Met) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250956 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.94C>A has been reported at a compound heterozygous state with a second pathogenic variant in the literature in at-least one individual affected with Cystic Fibrosis from California Cystic Fibrosis Newborn Screening (Kharrazi_2015, Prach_2013, Salinas_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, a different missense at this codon (p.Leu32Pro) was reported at a compound heterozygous state with a second pathogenic nonsense variant in an individual with CF (PMID: 25580864), but the clinical significance of p.Leu32Pro has not been established. The following publications have been ascertained in the context of this evaluation (PMID: 26574590, 23810505, 27214204). ClinVar contains an entry for this variant (Variation ID: 502597). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000670047	SCV001464066	uncertain significance	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing