Submissions for variant NM_001009944.3(PKD1):c.9634_9635delinsGC (p.Phe3212Ala)

dbSNP: rs1085307551

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489538	SCV000576704	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing	The c.9634_9635delTTinsGC variant in the PKD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.9634_9635delTTinsGC variant results in the replacement of the normal Phenylalanine residue at position 3212 with an Alanine residue, denoted p.Phe3212Ala. The c.9634_9635delTTinsGC variant is observed in 1/63130 (0.0015%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The c.9634_9635delTTinsGC variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.9634_9635delTTinsGC as a variant of uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470877	SCV002768190	uncertain significance	Polycystic kidney disease, adult type	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to alanine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 4 heterozygotes, 0 homozygotes). It was noted that this variant was annotated as p.(Phe3212Ser) and p.(Phe3212Val) in both v2 and v3. (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated PLAT domain (NCBI, DECIPHER, Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been classified as a variant of uncertain significance by a diagnostic laboratory in ClinVar. In addition, both NM_000296:c.9634T>G and NM_000296:c.9635T>C have been identified in an individual with polycystic kidney disease however, there is a possibility that these two variants are in fact a single event identical to NM_001009944.2:c.9634_9635delinsGC. In this same individual, a causative frameshift variant was also identified (PMID: 33964006). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign