ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.7280T>C (p.Ile2427Thr)

gnomAD frequency: 0.00001  dbSNP: rs398124492
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000082569 SCV000114611 uncertain significance not provided 2014-04-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004196 SCV001163032 likely pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272061 SCV001427150 likely pathogenic Polycystic kidney disease 4 2022-06-24 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intrafamilial variation of severity has been reported (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two unrelated individuals with autosomal recessive polycystic kidney disease (PMIDs: 15698423, 27225849). In addition, it has been regarded as VUS (older submission) and as likely pathogenic and pathogenic more recently (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_138694.3(PKHD1):c.10219C>T; p.(Gln3407*)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (segregation analysis by external laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae RCV001004196 SCV001588859 pathogenic Autosomal recessive polycystic kidney disease 2023-08-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. ClinVar contains an entry for this variant (Variation ID: 96419). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 15698423, 27225849). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs398124492, gnomAD 0.004%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2427 of the PKHD1 protein (p.Ile2427Thr).
Baylor Genetics RCV002272061 SCV004202270 likely pathogenic Polycystic kidney disease 4 2023-09-30 criteria provided, single submitter clinical testing

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