Submissions for variant NM_000492.4(CFTR):c.314T>A (p.Ile105Asn)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382997	SCV001581993	pathogenic	Cystic fibrosis	2024-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 105 of the CFTR protein (p.Ile105Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 25697318, 26574590, 27214204, 28830496; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53665). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001382997	SCV005076731	likely pathogenic	Cystic fibrosis	2024-04-10	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.314T>A (p.Ile105Asn) 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 251142 control chromosomes. c.314T>A has been reported in the literature in multiple compound heterozygous individuals affected with Cystic Fibrosis or CBAVD (e.g. DeWatcher_2017, Goubau_2009, Guiliani_2010, Lay-son_2014, Salinas_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28830496, 19318346, 20657600, 25697318, 27214204). ClinVar contains an entry for this variant (Variation ID: 53665). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005042143	SCV005666792	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826657	SCV002080118	pathogenic	CFTR-related disorder	2017-09-01	no assertion criteria provided	clinical testing

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