Submissions for variant NM_001009944.3(PKD1):c.8235T>G (p.Ser2745=)

gnomAD frequency: 0.00020  dbSNP: rs556575921

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000242143	SCV000305791	likely benign	not specified		criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254243	SCV001430235	benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
GeneDx	RCV002469088	SCV002765790	likely benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Fulgent Genetics, Fulgent Genetics	RCV002479964	SCV002804361	benign	Polycystic kidney disease, adult type	2021-07-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292479	SCV001480587	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ser2745= variant was identified in 2 of 160 proband chromosomes (frequency: 0.0125) from individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Watnick 1997). Affected individuals were discovered to have clusters of base pair substitutions in exons 23 and 25 in addition to the variant (c>8279T>C/M2760T, c>8282G>C/R2761P, c>8291T>C/M2764T c>8477T>C/I2826T, c>8287C>G/L2763V), and the variant segregated with disease in 1 kindred (Watnick 1997). In a study looking at the consequences of gene conversions in the PKD1 gene, pathogenicity was undetermined (Symmons 2008). The variant was also identified in dbSNP (ID: rs556575921) “With Likely benign allele”, ClinVar (classified likely benign by Prevention Genetics), LOVD 3.0 (1x), ADPKD Mutation Database (classified as highly likely pathogenic, exon 23 gene conversion (2)), and was not identified in COGR, and PKD1-LOVD databases. The variant was identified in control databases in 49 of 243470 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 39 of 14862 chromosomes (frequency: 0.003), Other in 1 of 5428 chromosomes (frequency: 0.0002), Latino in 6 of 33526 chromosomes (frequency: 0.0002), European Non-Finnish in 2 of 109758 chromosomes (frequency: 0.00002), and East Asian in 1 of 17192 chromosomes (frequency: 0.00006). 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 variant was identified in 1 individual with ADPKD in our laboratory, co-occurring with a pathogenic PKD2 variant (c.958C>T, p.Ala320X), increasing the likelihood the variant does not have clinical significance. The p.Ser2745= 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. 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 benign role for this variant. This variant is classified as likely benign.