Submissions for variant NM_000492.4(CFTR):c.853A>T (p.Ile285Phe)

gnomAD frequency: 0.00145  dbSNP: rs151073129

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000598331	SCV000697048	benign	not specified	2021-01-22	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.853A>T (p.Ile285Phe) 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. In contrast, a recently published in-silico tools based consensus classifier has predicted this variant to have a neutral impact (Michels_2019). The variant allele was found at a frequency of 0.00043 in 280644 control chromosomes, predominantly at a frequency of 0.0046 within the African subpopulation in the gnomAD database, including 1 homozygote. The combined allele frequency of the two most frequent pathogenic CF variants in Africans (i.e. c.2988+1G>A and p.F508del) that are found in up to 60% of all carriers (see in PMID 21474639) is 0.0038 in the gnomAD database. Therefore, the allele frequency of c.853A>T alone is much higher than combined frequency of the two most common pathogenic variants in the same subpopulation, supporting a benign role for this variant. The variant, c.853A>T, has been reported in the literature in an individual with chronic respiratory problems and a non-informative genotype (example, Schrijver 2005) and in an individual reportedly affected with Cystic Fibrosis also with a non-informative genotype (example, Pereira 2019). It was also reported in trans with a large CFTR promoter deletion in a presumably unaffected mother of a CF proband. The molecular diagnosis of CF in the proband was attributed to two other variants, namely the promoter deletion inherited from the mother and c.2988+1G>A inherited from the father (Hantash_2006). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=2)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Eurofins Ntd Llc (ga)	RCV000598331	SCV000700536	likely benign	not specified	2017-06-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000029547	SCV001137469	benign	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029547	SCV001597830	likely benign	Cystic fibrosis	2025-01-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257363	SCV002529738	likely benign	Hereditary pancreatitis	2020-11-09	criteria provided, single submitter	curation
Ambry Genetics	RCV000029547	SCV002675488	likely benign	Cystic fibrosis	2022-10-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477015	SCV002774136	likely benign	not provided	2021-08-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477014	SCV002797967	likely benign	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-09-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002477015	SCV003800282	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000029547	SCV004024501	likely benign	Cystic fibrosis	2023-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV002477015	SCV005441445	uncertain significance	not provided	2024-06-26	criteria provided, single submitter	clinical testing	Identified in an individual with chronic respiratory symptoms (PMID: 15858154); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34996830, 30996306, 16362824, 25087612, 15858154)
PreventionGenetics, part of Exact Sciences	RCV004532410	SCV004726993	likely benign	CFTR-related disorder	2023-01-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).