ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs121908790
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Total submissions: 11
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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 2022-07-13 criteria provided, single submitter clinical testing Variant summary: CFTR c.164+12T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational 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 higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0026 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), providing supporting evidence for a benign role. Another recent 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. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. 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.
Invitae 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: 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
PreventionGenetics, part of Exact Sciences RCV004537223 SCV004719372 uncertain significance CFTR-related disorder 2024-02-22 criteria provided, single submitter 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.
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

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