Submissions for variant NM_000492.4(CFTR):c.3908A>T (p.Asn1303Ile)

gnomAD frequency: 0.00006  dbSNP: rs397508636

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004512	SCV001163557	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009506	SCV001169601	pathogenic	CFTR-related disorder	2018-03-26	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577150	SCV002252626	likely pathogenic	Cystic fibrosis	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1303 of the CFTR protein (p.Asn1303Ile). This variant is present in population databases (rs397508636, gnomAD 0.02%). This missense change has been observed in individuals with CFTR-related conditions (PMID: 9598638, 10923036). ClinVar contains an entry for this variant (Variation ID: 53846). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 11788611). This variant disrupts the p.Asn1303 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21520337, 23951356, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577150	SCV002573871	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3, PM5_STR, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577150	SCV005040480	likely pathogenic	Cystic fibrosis	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3908A>T (p.Asn1303Ile) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249628 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3908A>T has been reported in the literature in at-least two individuals affected with Cystic Fibrosis and Congenital Bilateral Absence of the Vas Deferens (example, Clausters_2000). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a long burst duration and a long interburst interval of CFTR gating via patch-clamp electrophysiology (Berger_2002). Additionally, other variants at the Asn1303 residue have been reported as associated with disease (p.Asn1303Lys), suggesting that this codon is functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 11788611, 10923036, 21520337). ClinVar contains an entry for this variant (Variation ID: 53846). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV004566879	SCV005057452	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-04	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577150	SCV000679099	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530074	SCV001744655	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530074	SCV001970812	pathogenic	not provided		no assertion criteria provided	clinical testing