ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.1964+17G>T (rs201349527)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082532 SCV000114574 benign not specified 2013-06-14 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000082532 SCV000315780 likely benign not specified criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588326 SCV000699852 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.1964+17G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on the canonical splice donor site, but 4/5 splice prediction tools predict the gain of cryptic splice donor sites. ESEfinder predicts a gain of a binding motif for splicing enhancer SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 674/121292 control chromosomes (4 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0074681 (497/66550). This frequency is about 1.1 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this intronic variant may be a benign polymorphism found primarily in the non-Finnish Europeans. This variant was reported in at least one ARPKD patient without strong evidence for causality (Obeidova_BMC medical genetics_2015). In addition, one clinical diagnostic laboratory classified this variant as benign, without providing evidence to independently evaluate. Because of the limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.

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