Submissions for variant NM_000492.4(CFTR):c.416A>T (p.His139Leu)

dbSNP: rs76371115

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985694	SCV001134144	pathogenic	not provided	2022-08-15	criteria provided, single submitter	clinical testing	The CFTR c.416A>T (p.His139Leu) variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple compound heterozygous and homozygous individuals with classic CF (PMIDs: 32026723 (2020), 28546993 (2017), 15463866 (2003), 10834512 (2000), 10605524 (1999)). A retrospective study reported the variant as a common CF mutation in the Saudi population (PMID: 32026723 (2020). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577674	SCV001580422	pathogenic	Cystic fibrosis	2022-07-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 53910). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10605524, 10834512, 28546993). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 139 of the CFTR protein (p.His139Leu).
Genome-Nilou Lab	RCV000577674	SCV001822000	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577674	SCV002630487	likely pathogenic	Cystic fibrosis	2015-09-04	criteria provided, single submitter	clinical testing	The p.H139L variant (also known as c.416A>T and 548A>T), located in coding exon 4 of the CFTR gene, results from an A to T substitution at nucleotide position 416. The histidine at codon 139 is replaced by leucine, an amino acid with similar properties. In a Saudi Arabian cohort, three CF patients with pulmonary disease and pancreatic insufficiency were determined to be homozygous for this alteration (Banjar H, Ann Trop Paediatr 1999 Mar; 19(1):69-73). In another study, this variant was reportedly detected in trans with the CFTR p.S549R pathogenic mutation and was not detected in 200 control chromosomes (Kambouris M, Eur. J. Pediatr. 2000 May; 159(5):303-9). 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.
Baylor Genetics	RCV003466914	SCV004215779	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2022-04-21	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000577674	SCV004804873	pathogenic	Cystic fibrosis	2024-03-17	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577674	SCV005421971	pathogenic	Cystic fibrosis	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.416A>T (p.His139Leu) 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 250688 control chromosomes. c.416A>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Banjar_1999, Banjar_2020. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 1% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 10605524, 32026723, 38388235). ClinVar contains an entry for this variant (Variation ID: 53910). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577674	SCV000679462	not provided	Cystic fibrosis		no assertion provided	literature only