Submissions for variant NM_001009944.3(PKD1):c.8087T>G (p.Leu2696Arg)

dbSNP: rs201238819

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV003424051	SCV004142846	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PKD1: BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500666	SCV000592811	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Leu2696Arg variant was identified in 14 of 286 proband chromosomes (frequency: 0.049) from individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Phakdeekitcharoen 2001, Bataille 2011, Yu 2011). The p.Leu2696Arg variant was identified in the dbSNP (ID: rs201238819) with no known clinical significance. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server). The variant was identified in Exome Aggregation Consortium (March 14, 2016), in 42 of 19230 chromosomes (frequency: 0.002) or 10 of 8070 South Asians, 24 of 7400 European (Non-Finnish), 2 of 628 Latino, 5 of 1616 African and 1 of 178 Other populations and not found in East Asian and European (Finnish), increasing the likelihood this could be a low frequency benign variant. The variant was identified in the PKD Mutation Database and was classified as likely neutral. The p.Leu2696 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. In a study of 41 Thai probands with ADPKD and pathogenic variants in the replicated portion of the PKD1 gene, the p.Leu2696Arg variant was identified to occur in non-conservative region within the REJ domain, but its effect on the three-dimensional structure is unknown. Glutamic acid and arginine are observed in the corresponding positions of Fugu and murine polycystin-1, respectively, suggesting a noncritical role for a nonpolar residue at this location (Phakdeekitcharoen 2001). In ADPKD family studies, the variant was identified in a fetus with cystic kidneys resembling ADPKD on ultrasound however it co-occurred with a de novo PKD1 “likely pathogenic” variant (c.9222C>G, p.Asn3074Lys. The fetus was also identified to carry a HNF1β “highly likely pathogenic” variant (c.883C>T, p.Arg295Cys) which was also identified in the father and paternal grandmother who had cystic kidneys consistent with the HNF1β phenotype. The PKD1 p.Leu2696Arg variant was inherited from the mother with a normal renal phenotype. (Bergmann_2011_22034641). 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 Benign.