Submissions for variant NM_000492.4(CFTR):c.164+12T>C

gnomAD frequency: 0.00001  dbSNP: rs121908790

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855588	SCV000696856	likely benign	not specified	2024-06-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.164+12T>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 247964 control chromosomes, predominantly at a frequency of 0.0026 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00034 vs 0.013), allowing no conclusion about variant significance. c.164+12T>C was reported in the homozygous state in two unrelated Cystic Fibrosis patients of Pakistani origin born to consanguineous parents (Malone_1998). However, due to the use of older mutational scanning technologies in this study, the possibility of missed co-occurrences with pathogenic variants in these patients cannot be ruled out. A more recent study reported the variant in one patient of Saudi Arabian descent with classic CF in homozygous state. However, the patient was also homozygous for another pathogenic CFTR variant (c.3889dupT, p.Ser1297PhefsX5) present in cis with the variant of interest (Banjar_2017). Another study (Lascano-Vaca_2020), reported the variant in heterozygous state in 2 pediatric CF patients from Ecuador with a detailed genotype provided for one of the patients who also had known pathogenic variants F508del and W1098X, providing further supporting evidence for a benign role. . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12007216, 9482579, 22975760, 19645745, 12530290, 26436105, 32026723, 32143663). ClinVar contains an entry for this variant (Variation ID: 53302). Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga)	RCV000590024	SCV000700722	uncertain significance	not provided	2017-04-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000577399	SCV000915199	uncertain significance	Cystic fibrosis	2017-11-21	criteria provided, single submitter	clinical testing	The CFTR c.164+12T>C variant, which is often referred to as c.296+12T>C, has been reported in at least three studies and is found in a homozygous state in four individuals, three of whom were diagnosed with cystic fibrosis (CF) (Malone et al. 1998; Trujillano et al. 2015; Banjar et al. 2017). In a 6-year-old girl of Saudi descent, the c.164+12T>C variant was identified with a frameshift variant in a double homozygous state. The girl was reported to exhibit an earlier age of onset and lower BMI compared with other affected individuals (Banjar et al. 2017). The variant was shown to segregate with the disease in two families. The c.164+12T>C variant was absent from controls but is reported in a homozygous state in Exome Aggregation Consortium and Genome Aggregation Database. This variant is reported at a frequency of 0.019417 in the Gujarati Indian in Houston, Texas population of the 1000 Genomes Project, which is high but could be consistent with disease under-diagnosis in non-Caucasian populations. The evidence for this variant is limited. The c.164+12T>C variant is classified as unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577399	SCV001717509	benign	Cystic fibrosis	2024-01-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000577399	SCV001821984	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577399	SCV002574062	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, PP4, BS2, BP2, BP4
Ambry Genetics	RCV000577399	SCV002704562	likely benign	Cystic fibrosis	2023-06-28	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590024	SCV004564214	likely benign	not provided	2023-02-24	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577399	SCV000678908	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV000577399	SCV001453943	likely benign	Cystic fibrosis	2020-01-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537223	SCV004719372	uncertain significance	CFTR-related disorder	2024-02-22	no assertion criteria provided	clinical testing	The CFTR c.164+12T>C variant is predicted to interfere with splicing. This variant has been previously reported in homozygous state in individuals with cystic fibrosis (see for example: Trujillano et al. 2015. PubMed ID: 26436105 and Banjar et al. 2017. PubMed ID: 30805499). In one individual this variant was described as double homozygous, along with a second homozygous CFTR pathogenic variant (Banjar et al. 2017. PubMed ID: 30805499; ClinVarID:53841). This variant is reported in 0.26% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.