Submissions for variant NM_000492.4(CFTR):c.2735C>T (p.Ser912Leu)

gnomAD frequency: 0.00068  dbSNP: rs121909034

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007626	SCV001981582	uncertain significance	Cystic fibrosis	2017-10-03	reviewed by expert panel	research
Invitae	RCV000007626	SCV000074679	benign	Cystic fibrosis	2024-01-29	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	benign	not provided	2021-07-14	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.
Eurofins Ntd Llc (ga)	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	uncertain significance	Cystic fibrosis	2023-06-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007626	SCV001177395	likely benign	Cystic fibrosis	2021-11-10	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.
Illumina Laboratory Services, Illumina	RCV001158768	SCV001320423	uncertain significance	CFTR-related disorder	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.
Genome-Nilou Lab	RCV000007626	SCV001716382	likely benign	Cystic fibrosis	2021-05-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255257	SCV002529703	likely benign	Hereditary pancreatitis	2020-11-02	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007626	SCV002573999	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, BS3_MOD, BP2, BP4, BP6
PreventionGenetics, part of Exact Sciences	RCV001158768	SCV004721021	likely benign	CFTR-related disorder	2021-03-30	criteria provided, single submitter	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).
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