ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590024 SCV000696856 uncertain significance not provided 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The CFTR c.164+12T>C variant (alternatively also known as 296+12T>C and IVS2+12T>C) involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 4/5 splice prediction tools do not predict a significant impact on normal splicing. ESE finder predicts that this variant may abrogate the binding sites for splicing enhancers. However, these predictions have yet to be confirmed by functional studies. This variant was found in 45/103758 control chromosomes from ExAC (including one homozygote) at a frequency of 0.0004337, predominantly observed in the South Asian subpopulation at a frequency of 0.002854 (42/14718) which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant was recently reported in one patient of Saudi descent with classic CF in homozygous state, who was also homozygous for CFTR c.3889dupT (p.Ser1297PhefsX5) (Banjar_IJPAM_2017). Healthy parents and a sibling were heterozygous carriers for this variant and c.3889dupT in the same chromosome (in cis). This was the first case report of double homozygous of 2 different mutations in the CFTR gene in Saudi Arabia. In addition, this variant was found in two unrelated homozygous CF patients of Pakistani origin born to consanguineous parents in an older study (Malone_HM_1998). Only one of these 2 unrelated patients was comprehensively sequenced for all 27 exons; and four healthy siblings of the patient were heterozygous carriers. In Sickkids database reporting one of these patients, either parent is reported to be heterozygous carrier for this variant. To our knowledge, no published functional studies are available till date. Kaley_California Thoracic Society_2013 is a position paper that lists the variant as an atypical CF-causing mutation. Based on the available evidences, this variant is currently classified as a variant of uncertain clinical significance (VUS) until more clinical and functional data on the impact of this variant in the pathophysiology of CF or CFTR-RD become available.
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.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577399 SCV000678908 not provided Cystic fibrosis no assertion provided literature only

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