ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1210-11T>G (rs73715573)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507057 SCV000603012 pathogenic not specified 2017-06-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000381834 SCV000331080 other not provided 2016-05-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000309488 SCV000466510 likely benign Cystic fibrosis 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000381834 SCV000696826 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1210-11T>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the variant to slightly weaken a canonical splice acceptor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1118/104134 control chromosomes in ExAC, predominantly observed in the South Asian subpopulation at a frequency of 0.012128 (186/15336). This frequency is close to the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. However, this variant is marked as filtered non-pass variant in both ExAC and gnomAD, thus this frequency data needs to be taken in caution. One clinical diagnostic laboratory classified this variant as likely pathogenic, however is likely to be a mistaken entry, while another one lab classified this variant as likely benign, and another lab classified it as clinically benign, all without evidence for independent evaluaiton. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155471 SCV000205163 likely pathogenic Cystic fibrosis; Congenital bilateral absence of the vas deferens 2014-05-01 criteria provided, single submitter clinical testing The c.1210-34TG[12]T[5] in intron 9 of CFTR is a variant of the polymorphic TG[n ]T[m] region adjacent to exon 10. The TG[12]T[5] allele has been identified in 5 .9% (17/290) of Ashkenazi Jewish chromosomes, 3% (47/1472) of East Asian chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g/), and is known to affect mRNA splicing (Chu 1993). Studies have shown that lo nger TG repeat sizes (TG11, 12 and 13) in individuals with T[5] have a greater s usceptibility to disease than those with smaller TG repeat sizes when present in trans with a pathogenic CFTR variant (Chu 1992, Cuppens 1998, Groman 2004, Radp our 2007). The associated CF-related symptoms are congenital bilateral absence o f the vas deferens (CBAVD), male infertility, mild to classic forms of cystic fi brosis, with severity depending of the CF variant on the opposite allele (Chillo n 1995). In summary, the 1210-34TG[12]T[5] variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. AC MG/AMP Criteria applied: PM3_Strong, PP3, PP4.

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