ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.164+12T>C (rs121908790)

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Total submissions: 6
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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 2021-05-28 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. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590024 SCV000700722 uncertain significance not provided 2017-04-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2020-12-07 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

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