Submissions for variant NM_000492.4(CFTR):c.494T>C (p.Leu165Ser)

dbSNP: rs397508736

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000576939	SCV000924249	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
CFTR-France	RCV000576939	SCV001169316	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000576939	SCV002642593	pathogenic	Cystic fibrosis	2024-05-22	criteria provided, single submitter	clinical testing	The p.L165S pathogenic mutation (also known as c.494T>C), located in coding exon 5 of the CFTR gene, results from a T to C substitution at nucleotide position 494. The leucine at codon 165 is replaced by serine, an amino acid with dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other CFTR variant(s) in individual(s) who met clinical criteria for cystic fibrosis; in at least one instance, the variants were identified in trans (Calcedo R et al. Hum Gene Ther Clin Dev, 2013 Sep;24:108-15; Gaitch N et al. Pancreatology Apr;2016:515-22; De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142). This variant has also been reported in multiple individuals with an elevated sweat chloride level and has <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 05/20/2024; Raraigh KS et al. Am J Hum Genet, 2018 Jun;102:1062-1077). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576939	SCV005062097	pathogenic	Cystic fibrosis	2024-03-09	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.494T>C (p.Leu165Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249460 control chromosomes. c.494T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project (example, McCague_2019). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 30888834). ClinVar contains an entry for this variant (Variation ID: 53976). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005042149	SCV005673280	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-03-11	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000576939	SCV000679150	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001826690	SCV002080154	pathogenic	CFTR-related disorder	2021-07-29	no assertion criteria provided	clinical testing