ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.6777C>T (p.Phe2259=) (rs140065359)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153712 SCV000203270 benign not specified 2014-01-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000336710 SCV000464072 uncertain significance Autosomal recessive polycystic kidney disease 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000336710 SCV000557639 benign Autosomal recessive polycystic kidney disease 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000153712 SCV000918003 benign not specified 2017-12-21 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.6777C>T (p.Phe2259Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1516/276908 control chromosomes (12 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.014629 (377/25770). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, by applying ACMG rules (BS1, BS2, BP6, BP7) this variant is classified as benign.

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