Submissions for variant NM_138694.4(PKHD1):c.658G>A (p.Asp220Asn)

gnomAD frequency: 0.00015  dbSNP: rs199897497

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593464	SCV000702825	uncertain significance	not provided	2016-10-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001163885	SCV001325970	uncertain significance	Autosomal recessive polycystic kidney disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001163885	SCV001598273	likely benign	Autosomal recessive polycystic kidney disease	2024-01-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935596	SCV004763303	uncertain significance	PKHD1-related condition	2023-12-19	criteria provided, single submitter	clinical testing	The PKHD1 c.658G>A variant is predicted to result in the amino acid substitution p.Asp220Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000593464	SCV001549257	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PKHD1 p.Asp220Asn variant was not identified in the literature but was identified in dbSNP (ID: rs199897497) and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics). The variant was identified in control databases in 65 of 282198 chromosomes at a frequency of 0.0002303 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 36 of 25124 chromosomes (freq: 0.001433), European (non-Finnish) in 26 of 128652 chromosomes (freq: 0.000202), Other in 1 of 7192 chromosomes (freq: 0.000139), African in 1 of 24924 chromosomes (freq: 0.00004) and Latino in 1 of 35402 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Asp220 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.