Submissions for variant NM_138694.4(PKHD1):c.325G>A (p.Ala109Thr)

gnomAD frequency: 0.00035  dbSNP: rs143979330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179009	SCV000231198	benign	not specified	2015-04-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000288301	SCV000464128	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000288301	SCV001000631	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292146	SCV001480697	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Ala109Thr variant was not identified in the literature nor was it identified in the Geneinsight-COGR and LOVD 3.0 databases. The variant was identified in ClinVar (classification benign by Emory Genetics and uncertain significance by Illumina), and the RWTH AAachen University ARPKD database (unclassified). The variant was identified in control databases in 243 of 277130 chromosomes at a frequency of 0.000877 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following population at a frequency greater than 1%: East Asian in 204 of 18864 chromosomes (freq: 0.011). The p.Ala109Thr 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.
Natera, Inc.	RCV000288301	SCV002083417	likely benign	Autosomal recessive polycystic kidney disease	2017-05-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955075	SCV004768145	benign	PKHD1-related disorder	2019-02-22	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).