ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000586236 SCV000603046 benign not provided 2017-06-13 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000007626 SCV000074679 benign Cystic fibrosis 2017-12-28 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000007626 SCV000886880 benign Cystic fibrosis 2019-01-31 criteria provided, single submitter clinical testing
OMIM RCV000007626 SCV000027827 benign Cystic fibrosis 2005-05-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506704 SCV000601079 likely benign not specified 2016-12-05 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

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