Submissions for variant NM_001009944.3(PKD1):c.2534T>C (p.Leu845Ser)

dbSNP: rs199476100

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000712602	SCV000843119	pathogenic	not provided	2017-11-29	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761309	SCV000891289	likely pathogenic	Polycystic kidney disease 3 with or without polycystic liver disease	2018-03-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000008689	SCV000894071	pathogenic	Polycystic kidney disease, adult type	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000712602	SCV000928064	pathogenic	not provided	2018-11-20	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000008689	SCV001251270	likely pathogenic	Polycystic kidney disease, adult type	2020-02-05	criteria provided, single submitter	research	PS1, PP3, PP4
Molecular Biology Laboratory, Fundació Puigvert	RCV000008689	SCV001425172	likely pathogenic	Polycystic kidney disease, adult type	2020-02-01	criteria provided, single submitter	research
GeneDx	RCV000712602	SCV001982055	pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10854095, 22508176, 10364515, 25266109, 15772804, 23300259, 22383692, 26632257, 31740684, 30816285, 33454723, 35783601, 33532864, 37909612, Durkie2023[paper], 38224954, 38541974, 36186434, 26139440)
3billion, Medical Genetics	RCV000008689	SCV003841436	pathogenic	Polycystic kidney disease, adult type	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008206). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26139440). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10364515, 15772804, 22383692, 26139440). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15772804, 22383692). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000008689	SCV005184177	pathogenic	Polycystic kidney disease, adult type	2024-07-19	criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PM6+PP1_Strong+PP4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000712602	SCV005197162	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000008689	SCV000028898	pathogenic	Polycystic kidney disease, adult type	1999-07-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292482	SCV001480590	likely pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Leu845Ser variant was identified in 4 of 346 proband chromosomes (frequency: 0.012) from individuals or families of Chinese and Finnish ethnicity with ADPKD and was not identified in 420 control chromosomes from healthy individuals (Audrezet 2015, Liu 2015, Peltola 2005, Thomas 1999). Thomas et al (1999) identified the p.Leu845Ser variant in one affected individual and was not identified in the patient’s unaffected daughter. The variant was also identified in dbSNP (ID: rs199476100) as “With Pathogenic allele”, ClinVar database as pathogenic by OMIM and in ADPKD Mutation Database as highly likely pathogenic. The variant was not identified in GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, databases nor was it identified in the 1000 Genomes and the NHLBI GO Exome Sequencing Projects. The variant was identified in control databases in 1 of 226770 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Leu845Ser residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Leu845Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant predicts a change from a neutral and hydrophobic Leu to a polar Ser at position 845, six residues N-terminal to the start of PKD domain 2 (Thomas 1999). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the Polycystin cation channel functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004739297	SCV005362285	pathogenic	PKD1-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The PKD1 c.2534T>C variant is predicted to result in the amino acid substitution p.Leu845Ser. This variant has been repeatedly reported in unrelated patients with autosomal dominant polycystic kidney disease (ADPKD) and it was widely documented as a “highly likely pathogenic” variant (Thomas et al. 1999. PubMed ID: 10364515; Liu et al. 2015. PubMed ID: 26632257; Peltola et al. 2005. PubMed ID: 15772804; http://pkdb.mayo.edu). This variant is reported in 0.0085% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.