ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1210-6delT (rs1805177)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588295 SCV000696829 uncertain significance not provided 2017-06-20 criteria provided, single submitter clinical testing Variant summary:The CFTR c.6T_TG11 (also referred to as c.1210-6delT) variant involves the deletion of an intronic thymine nucleotide from a poly-T tract that is adjacent to a polymorphic TG repeat motif, where 11 TG repeats are present, forming the haplotype notated as 6T_TG11. The 11 TG repeats are normal in the population and considered the reference number of repeats, whereas the poly-T tract typically contains 7 thymine nucleotides and is considered the reference number of thymine. Inheritance of decreased poly-T tracts (such as 5T or 6T) in combination with an increased number TG repeats (such as 13 TG) has been associated with a decreased expression of full length CFTR mRNA. One in silico tool predicts a benign outcome for this variant. The 6T variant in isolation was found in the large control database at a frequency of 0.0001603 (16/99808 control chromosomes), predominantly in the East Asian subpopulation (12/7664 control chromosomes; 0.001566), neither of which exceeds the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). However, the frequency of the full haplotype (6T_TG11) was not specified in ExAC, thus the frequency of this particular allele is unknown. The variant of interest has been reported in controls and non-CF patients in the literature, without strong evidence for causality and often without clear indication of TG allele number. The variant has not, to our knowledge, been evaluated for functional impact by in vivo/vitro studies. The 6T variant has been reported in the UMD database in two heterozygous patients: one diagnosed with CBAVD who also carries the pathogenic CFTR variant c.2128A>T (p.Lys710X), and another patient who is diagnosed with cystic fibrosis, though a second mutation was not reported. In addition, the number of TG repeats in the haplotype of each of these patients was not provided, making assessment of the pathogenicity of the full allele difficult. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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