Submissions for variant NM_001009944.3(PKD1):c.580G>A (p.Ala194Thr)

gnomAD frequency: 0.00109  dbSNP: rs769369111

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001289132	SCV001476745	benign	not specified	2019-09-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001564252	SCV001787388	likely benign	not provided	2021-04-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002499509	SCV002813770	likely benign	Polycystic kidney disease, adult type	2021-07-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001564252	SCV004142916	benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292145	SCV001480696	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ala194Thr variant was not identified in the literature nor was it identified in the ClinVar or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs769369111), LOVD 3.0 (1x), and ADPKD Mutation Database (as likely neutral). The variant was identified in control databases in 185 of 159710 chromosomes at a frequency of 0.001, 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: European in 140 of 64822 chromosomes (freq: 0.002), African in 4 of 14698 chromosomes (freq: 0.0003), Other in 2 of 4522 chromosomes (freq: 0.0004), Latino in 15 of 24570 chromosomes (freq: 0.0006), Ashkenazi Jewish in 6 of 8192 chromosomes (freq: 0.0007), Finnish in 15 of 8726 chromosomes (freq: 0.002), and South Asian in 3 of 22636 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian population. 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 p.Ala194 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001564252	SCV001931528	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001564252	SCV001969505	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001564252	SCV002036133	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003928825	SCV004745279	likely benign	PKD1-related disorder	2020-06-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).