Submissions for variant NM_000492.4(CFTR):c.3299A>C (p.Gln1100Pro)

dbSNP: rs397508535

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000577192	SCV000788838	likely pathogenic	Cystic fibrosis	2017-01-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000577192	SCV000886271	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004493	SCV001163538	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577192	SCV001361658	pathogenic	Cystic fibrosis	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3299A>C (p.Gln1100Pro) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251108 control chromosomes. c.3299A>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Mota_2018, Siryani_2015, Alonso_2007, Chillon_1994). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: four submitters have classified the variant as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577192	SCV001587681	pathogenic	Cystic fibrosis	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1100 of the CFTR protein (p.Gln1100Pro). This variant is present in population databases (rs397508535, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 16240056, 26208274, 27145507, 30232781). ClinVar contains an entry for this variant (Variation ID: 53711). 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%. This variant disrupts the p.Gln1100 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 23240968), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000577192	SCV002611982	pathogenic	Cystic fibrosis	2024-06-13	criteria provided, single submitter	clinical testing	The p.Q1100P pathogenic mutation (also known as c.3299A>C), located in coding exon 20 of the CFTR gene, results from an A to C substitution at nucleotide position 3299. The glutamine at codon 1100 is replaced by proline, an amino acid with similar properties. This variant has been identified in the homozygous state and in conjunction with other CFTR variant(s) in individuals with features consistent with cystic fibrosis (Guardiano M et al. Rev Port Pneumol, 2005;11:381-406; Essawi O et al. Dis. Markers, 2015;2015:458653; Mota LR et al. Mol Biol Rep, 2018 Dec;45:2045-2051; Ambry internal data). In multiple assays testing CFTR function, this variant showed functionally abnormal results (Ramalho SS et al. Int J Mol Sci, 2021 Dec;23:; Bihler H et al. J Cyst Fibros, 2024 Feb;:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474574	SCV004213446	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-13	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000577192	SCV004239074	likely pathogenic	Cystic fibrosis	2023-09-13	criteria provided, single submitter	clinical testing	CFTR c.3299A>C has been identified in multiple individuals with elevated sweat chloride concentration and features of cystic fibrosis (CF) who also have a second CF-causing CFTR variant, although the phase of these variants has not been confirmed. This CFTR variant (rs397508535) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 1/251108 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar (Variation ID: 53711). A single peer-reviewed functional study indicates that this variant may impact CFTR trafficking. The glutamine residue at this position is evolutionarily conserved across most species assessed, but not fish. We consider CFTR c.3299A>C to be likely pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577192	SCV000679059	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001831772	SCV002083628	pathogenic	CFTR-related disorder	2020-11-11	no assertion criteria provided	clinical testing