Submissions for variant NM_001009944.3(PKD1):c.107C>A (p.Pro36His)

gnomAD frequency: 0.01538  dbSNP: rs560049593

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001697689	SCV000530493	benign	not provided	2019-09-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22008521, 18640754)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755607	SCV000604763	benign	Polycystic kidney disease, adult type	2020-02-28	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254212	SCV001430281	likely benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
Breakthrough Genomics, Breakthrough Genomics	RCV001697689	SCV005219023	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003891863	SCV000305670	benign	PKD1-related disorder	2019-07-23	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291862	SCV000592726	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Pro36His variant was identified in 20 of 616 proband chromosomes (frequency: 0.03) from individuals or families with ADPKD (with or without family history), and was not identified in 150 control chromosomes from healthy individuals (Reed 2008, Bataille 2011, Peltola 2005, Rossetti 2012). Reed et al. could not classify the variant however the conservation score associated the variant with some evolutionary variability (Reed 2008). The variant was identified in dbSNP (ID: rs560049593) as “With other allele”, ClinVar (classified benign by ARUP, and likely benign by Prevention Genetics and GeneDx), and ADPKD Mutation Database (classified as likely neutral). The variant was not identified in PKD1-LOVD or LOVD 3.0. The variant was identified in control databases in 398 of 26042 chromosomes (3 homozygous) at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 44 of 8250 chromosomes (freq: 0.005), Other in 18 of 744 chromosomes (freq: 0.02), Latino in 2 of 396 chromosomes (freq: 0.005), European Non-Finnish in 266 of 13680 chromosomes (freq: 0.02), Ashkenazi Jewish in 1 of 224 chromosomes (freq: 0.004), European Finnish in 67 of 1126 chromosomes (freq: 0.06); it was not observed in the East Asian, and South Asian populations. The p.Pro36 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His to the protein; this information is not very predictive of 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 this variant meets our laboratory criteria to be classified as benign.