ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs376987651
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665223 SCV000789301 pathogenic Autosomal recessive polycystic kidney disease 2017-01-26 criteria provided, single submitter clinical testing
Invitae RCV000665223 SCV002228297 pathogenic Autosomal recessive polycystic kidney disease 2024-01-09 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the PKHD1 mRNA. The next in-frame methionine is located at codon 9. This variant is present in population databases (rs376987651, gnomAD 0.004%). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 27225849). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550469). This variant disrupts a region of the PKHD1 protein in which other variant(s) (p.Leu8Pro) have been observed in individuals with PKHD1-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002477480 SCV002776388 likely pathogenic Polycystic kidney disease 4 2021-10-26 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292012 SCV001481087 pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKHD1 p.Met1? variant was identified in 3 of 260 proband chromosomes (frequency: 0.0115) from individuals or families with Autosomal Recessive PKD (Melchionda, 2016). The affected individuals found to carry the p.Met? variant were descried as perinatal (alive), 8 year old, and neonatal demise (Melchionda, 2016). The variant was also identified in dbSNP (ID: rs376987651) as NA, and LOVD 3.0 databases. The variant was not identified in ClinVar, GeneInsight-COGR, RWTH AAachen University ARPKD databases. The variant was identified in control databases in 4 of 246088 chromosomes at a frequency of 0.000016 (Genome Aggregation Consortium Feb 27, 2017). The c.1A>G variant occurs in the first base of the exon. The c.1A>G p.Met1? variant occurs in the first base of the translation initiation site (the Methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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