Submissions for variant NM_001009944.3(PKD1):c.12448C>T (p.Arg4150Cys)

dbSNP: rs1282668884

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000992559	SCV001144958	pathogenic	not provided	2019-06-28	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
Fulgent Genetics, Fulgent Genetics	RCV001536035	SCV001752728	pathogenic	Polycystic kidney disease, adult type	2022-05-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000992559	SCV002765616	uncertain significance	not provided	2022-06-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31157564, 17574468, 25029430, 22508176, 22383692, 23431072)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292454	SCV001481000	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg4150Cys variant was identified in 3 of 1860 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individuals (Audrezet 2012, Garcia-Gonzalez 2007, Hwang 2016, Rossetti 2012). The variant was also identified in ADPKD Mutation Database (as highly likely pathogenic). The variant was not identified in the dbSNP, ClinVar, 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.Arg4150 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356997	SCV001552314	uncertain significance	Autosomal dominant polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg4150Cys variant was identified in 3 of 1860 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individuals (Audrezet 2012, Garcia-Gonzalez 2007, Hwang 2016, Rossetti 2012). The variant was also identified in ADPKD Mutation Database (as highly likely pathogenic). The variant was not identified in the dbSNP, ClinVar, 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.Arg4150 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.
PreventionGenetics, part of Exact Sciences	RCV004740532	SCV005346158	pathogenic	PKD1-related disorder	2024-04-09	no assertion criteria provided	clinical testing	The PKD1 c.12448C>T variant is predicted to result in the amino acid substitution p.Arg4150Cys. This variant has been reported in unrelated families with autosomal dominant polycystic kidney disease (ADPKD) and it is classified as a “highly likely pathogenic” variant (reported as R4149C at Suppl. Table 4 at Garcia-Gonzalez et al. 2007. PubMed ID: 17574468; Suppl. Table S5 at Rossetti et al. 2012. PubMed ID: 22383692; Suppl. Table 1 at Cornec-Le Gall et al. 2013. PubMed ID: 23431072). Of note, a different change at the same codon (c.12449G>A, p.Arg4150His) has also been reported in one patient with ADPKD (Mori et al. 2016. PubMed ID: 26920127; http://pkdb.mayo.edu). At PreventionGenetics, we have previously found this variant in unrelated patients tested for polycystic kidney disease. The c.12448C>T (p.Arg4150Cys) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.