Submissions for variant NM_001009944.3(PKD1):c.3785A>G (p.His1262Arg)

dbSNP: rs1057518976

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501988	SCV000592766	uncertain significance	not specified	2016-05-26	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000501988	SCV000614499	uncertain significance	not specified	2016-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV002510884	SCV002820820	uncertain significance	not provided	2024-05-14	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; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002521461	SCV003715108	uncertain significance	Inborn genetic diseases	2021-12-27	criteria provided, single submitter	clinical testing	The c.3785A>G (p.H1262R) alteration is located in exon 15 (coding exon 15) of the PKD1 gene. This alteration results from an A to G substitution at nucleotide position 3785, causing the histidine (H) at amino acid position 1262 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501988	SCV003934678	uncertain significance	not specified	2023-05-26	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.3785A>G (p.His1262Arg) results in a non-conservative amino acid change located in the polycystin cation channel domain (IPR006228) positioned within the 7th PKD repeat domain (IPR000601, UniProt) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242174 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3785A>G in individuals affected with Polycystic Kidney Disease 1 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV002510884	SCV004227504	uncertain significance	not provided	2022-11-09	criteria provided, single submitter	clinical testing	PM2_supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415037	SCV000493048	likely pathogenic	Polycystic kidney disease; Abnormality of the kidney; Multicystic kidney dysplasia	2013-11-28	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739716	SCV005349427	uncertain significance	PKD1-related disorder	2024-08-30	no assertion criteria provided	clinical testing	The PKD1 c.3785A>G variant is predicted to result in the amino acid substitution p.His1262Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.