Submissions for variant NM_001009944.3(PKD1):c.1396G>A (p.Val466Met)

dbSNP: rs2855341

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000518467	SCV000614488	likely pathogenic	not provided	2016-06-28	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254311	SCV001430263	uncertain significance	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
GeneDx	RCV000518467	SCV002567733	uncertain significance	not provided	2022-02-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32398770, 26453610, 31740684, 33437033, 17582161, 29270497)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470893	SCV002768234	likely pathogenic	Polycystic kidney disease, adult type	2022-02-02	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 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated C-type lectin domain (UniProt). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.(Val466Leu)) has been reported as a VUS, and was identified in an individual with PKD who also had another splice variant in the PKD1 gene (pkdb.org, PMID: 17582161). (I) 0804 - This variant has previously been described as a variant of uncertain significance in multiple independent cases with consistent phenotype despite being absent in the general population. This variant has been reported as a VUS and as likely pathogenic, and has been described in at least five unrelated individuals with polycystic kidney disease (PKD) (ClinVar, pkdb.org, PMID: 17582161, PMID: 31740684, PMID: 26453610, PMID: 29270497). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been reported to segregate in a family, however there is insufficient evidence of each relative's phenotype (PMID: 26453610). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292370	SCV001480774	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Val466Met variant was identified in 2 of 844 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Rosetti, 2007,Hwang, 2016). The variant was also identified in dbSNP (ID: rs2855341) as “With Likely pathogenic allele”, ClinVar (classified as likely pathogenic by Athena Diagnostics), ADPKD Mutation Database (classified as indeterminate, including a reference to the unpublished classification from Athena Diagnostics and to Rosetti, 2007).The variant was not identified in the LOVD 3.0 or PKD1-LOVD databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Val466Met variant was observed in one ADPKD individual in a study which observed a second individual with a substitution to leucine at the same residue, suggesting significance, however both changes are highly conservative and the residue is considered to be not well conserved, so both substitutions were classified as indeterminate (Rosetti, 2007). The variant has been observed in a case with an alternate molecular basis for disease (PKD1 c.12596_12600dup, p.Leu4201*). The p.Val466 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino"	RCV002470893	SCV004040466	likely pathogenic	Polycystic kidney disease, adult type	2023-07-03	no assertion criteria provided	clinical testing