Submissions for variant NM_000492.4(CFTR):c.443T>A (p.Ile148Asn)

dbSNP: rs35516286

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593590	SCV000706678	uncertain significance	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000576960	SCV000886276	uncertain significance	Cystic fibrosis	2020-09-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004430	SCV001163475	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000576960	SCV001822002	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576960	SCV002954751	uncertain significance	Cystic fibrosis	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with asparagine at codon 148 of the CFTR protein (p.Ile148Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with atypical cystic fibrosis and cystic fibrosis (PMID: 15480987, 28771972). ClinVar contains an entry for this variant (Variation ID: 53949). 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: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576960	SCV003934547	pathogenic	Cystic fibrosis	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.443T>A (p.Ile148Asn) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250526 control chromosomes. c.443T>A has been reported in the literature in the presumed compound heterozygous state in multiple individuals affected with Cystic Fibrosis or atypical Cystic Fibrosis (example, Hirtz_2004, Silva_2016,_Silva_2020, Maciel_2020). These data indicate that the variant is 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 5.75% 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: 38388235, 32084388, 33111836, 11504857, 15480987, 10571949, 28771972, 25735457, 33424627, 26898888, 32819855, 26429520). ClinVar contains an entry for this variant (Variation ID: 53949). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV004566883	SCV005057426	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-02	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000576960	SCV000679497	not provided	Cystic fibrosis		no assertion provided	literature only