Submissions for variant NM_000492.4(CFTR):c.1516A>G (p.Ile506Val)

gnomAD frequency: 0.00034  dbSNP: rs1800091

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007551	SCV000284995	benign	Cystic fibrosis	2024-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000245320	SCV000304472	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000245320	SCV000331550	benign	not specified	2016-07-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759754	SCV000603019	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	The CFTR c.1516A>G; p.Ile506Val variant (rs1800091) is reported in the literature in at least two individuals with a severe pathogenic variant on the opposite allele and no symptoms of cystic fibrosis (Kobayashi 1990). The p.Ile506Val variant is reported in ClinVar (Variation ID: 7131), and is found in the general population with an overall allele frequency of 0.036% (101/282,660 alleles) in the Genome Aggregation Database. The isoleucine at codon 506 highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.57). Additionally, other amino acid substitutions at this codon (Leu, Met, Ser, Thr) have been reported in individuals with cystic fibrosis (Castellani 2008, Chevalier-Porst 1994, Deufel 1994, Strandvik 2001). While this variant is unlikely to be associated with classic cystic fibrosis, since an association with CFTR- related disorder cannot be excluded p.Ile506Val is classified as a variant of uncertain clinical significance. References: Castellani C et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96. PMID: 18456578 Chevalier-Porst F et al. Mutation analysis in 600 French cystic fibrosis patients. J Med Genet. 1994 Jul;31(7):541-4. PMID: 7525963 Deufel A et al. Three novel mutations (I506S, S466X, 1651A-->T) in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) detected in patients of southern German descent. Hum Mutat. 1994;3(1):64-6. PMID: 7509683 Kobayashi K et al. Benign missense variations in the cystic fibrosis gene. Am J Hum Genet. 1990 47(4):611-5. PMID: 1977306 Strandvik B et al. Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Genet Test. 2001 5(3):235-42. PMID: 11788090
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759754	SCV000889286	benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007551	SCV001172259	benign	Cystic fibrosis	2015-02-12	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV000007551	SCV001653485	uncertain significance	Cystic fibrosis	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000759754	SCV001772723	likely benign	not provided	2021-04-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27131402, 19914443, 33260873, 1977306, 32026723, 19324992, 19359498, 22975760)
Sema4, Sema4	RCV001282755	SCV002529677	benign	Hereditary pancreatitis	2020-04-28	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000759754	SCV005050845	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	CFTR: PM5
OMIM	RCV000007551	SCV000027752	benign	Cystic fibrosis	1990-10-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000007551	SCV001453963	uncertain significance	Cystic fibrosis	2017-11-17	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000759754	SCV001744213	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759754	SCV001971580	likely benign	not provided		no assertion criteria provided	clinical testing