Submissions for variant NM_001009944.3(PKD1):c.1023C>T (p.Ala341=)

gnomAD frequency: 0.03937  dbSNP: rs11643513

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000242828	SCV000305662	benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000576737	SCV000604705	benign	Polycystic kidney disease, adult type	2020-05-11	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000576737	SCV000677386	benign	Polycystic kidney disease, adult type	2017-05-02	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254220	SCV001430161	benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
GeneDx	RCV001706300	SCV001828758	benign	not provided	2019-09-25	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291864	SCV000592733	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ala341Ala variant was identified in 36 of 1504 proband chromosomes (frequency: 0.024) from French, Australian, Dutch, British, and American individuals or families with ADPKD (Bataille 22008521, McCluskey 2002, Peters 2001, Rossetti 2001, Tan 2009, Rossetti 2012). The variant was identified in dbSNP (ID: rs11643513) as “NA”, ADPKD Mutation Database (classification likely neutral), but was not in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 130 of 5000 chromosomes (frequency: 0.026), HAPMAP populations: AMR in 66 of 694 chromosomes (frequency: 0.0951) and EUR in 53 of 1006 chromosomes (frequency: 0.0527)/-SAS in 9 or 978 chromosomes (frequency: 0.0092), and in the Exome Aggregation Consortium database (March 14, 2016) in all populations except East Asian: European (Finnish) in 2 of 8 chromosomes (frequency: 0.25), Latino in 18 of 154 chromosomes (frequency: 0.1169), Other in 6 of 120 chromosomes (frequency: 0.05), European (Non-Finnish) in 132 of 2930 chromosomes (frequency: 0.0461), South Asian in 109 of 6226 chromosomes (frequency: 0.0174) and African in 5 of 436 chromosomes (frequency: 0.0115), increasing the likelihood this could be a low frequency benign variant. However we are not able to rule out that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala341Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001706300	SCV002037075	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000242828	SCV002037563	benign	not specified		no assertion criteria provided	clinical testing