ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2735C>T (p.Ser912Leu) (rs121909034)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000007626 SCV000074679 benign Cystic fibrosis 2020-12-04 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000007626 SCV000267253 likely benign Cystic fibrosis 2016-03-18 criteria provided, single submitter reference population
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586236 SCV000601079 likely benign not provided 2019-10-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506704 SCV000603046 benign not specified 2018-10-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586236 SCV000696917 benign not provided 2017-07-19 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2735C>T (p.Ser912Leu) variant involves the alteration of a not conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 279/304800 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation in gnomAD at a frequency of 0.017041 (173/10152). This frequency is about 1.3 times the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. However, it needs to be noted that this observation needs to take into account the nature of this population having lower genetic heterogeneity. This variant has been reported in multiple affected individuals; however, many of the reported cases also carried p.G1244V in cis or in cis with another potentially pathogenic variant. Functional data shows that the variant of interest, alone, acts comparable to wild type function, however, in cis with another potentially pathogenic variant such as G1244V (shown to have pathogenic properties, in isolation) drastically affects functionality (Clain_2005). In addition, an asymptomatic male was compound heterozygous (in trans) for this variant and a pathogenic (p.R709X) was reported (Clain_2005), supporting for benign outcome. Furthermore, multiple clinical diagnostic laboratories/reputable databases and publications (Clain_2005 and Zietkiewicz_2014) cite the variant of interest in isolation as Benign. Therefore, taken all together, variant of interest in isolation is classified as benign, however, one must take into consideration when the variant of interest is in a complex allele with another potentially pathogenic CFTR variant (in cis), the variant of interest may act as a modifier of pathogenicity.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000586236 SCV000700547 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing
GeneDx RCV000506704 SCV000730528 likely benign not specified 2018-01-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Johns Hopkins Genomics, Johns Hopkins University RCV000007626 SCV000886880 benign Cystic fibrosis 2019-01-31 criteria provided, single submitter clinical testing
Mendelics RCV000007626 SCV001137486 benign Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016438 SCV001177395 likely benign Inborn genetic diseases 2018-07-05 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification
Illumina Clinical Services Laboratory,Illumina RCV001158768 SCV001320423 uncertain significance CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Nilou-Genome Lab RCV000007626 SCV001716382 likely benign Cystic fibrosis 2021-05-18 criteria provided, single submitter clinical testing
OMIM RCV000007626 SCV000027827 benign Cystic fibrosis 2005-05-01 no assertion criteria provided literature only
Natera, Inc. RCV000007626 SCV001455994 benign Cystic fibrosis 2019-08-05 no assertion criteria provided clinical testing

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