Submissions for variant NM_001009944.3(PKD1):c.112C>G (p.Leu38Val)

dbSNP: rs1030433875

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003169775	SCV003865079	uncertain significance	Inborn genetic diseases	2023-01-24	criteria provided, single submitter	clinical testing	The c.112C>G (p.L38V) alteration is located in exon 1 (coding exon 1) of the PKD1 gene. This alteration results from a C to G substitution at nucleotide position 112, causing the leucine (L) at amino acid position 38 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001358432	SCV004030847	uncertain significance	not provided	2023-02-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358432	SCV001554161	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PKD1 p.Leu38Val variant was not identified in the literature nor was it identified in the following databases: dbSNP, ClinVar, COGR, LOVD 3.0, ADPKD Mutation Database, PKD1-LOVD, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The variant was identified in the Genome Aggregation Database (Feb 27, 2017) in 2 of 26188 chromosomes (frequency: 0.00008) in the European Non Finnish population in 2 of 13706 chromosomes (frequency: 0.0001). 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.Leu38 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Val variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.