Submissions for variant NM_138694.4(PKHD1):c.11224G>A (p.Ala3742Thr)

gnomAD frequency: 0.00005  dbSNP: rs557211301

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463053	SCV000557645	benign	Autosomal recessive polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000463053	SCV001327045	uncertain significance	Autosomal recessive polycystic kidney disease	2018-01-12	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357091	SCV001552438	likely benign	not provided		no assertion criteria provided	clinical testing	The PKHD1 p.A3742T variant was not identified in the literature but was identified in dbSNP (ID: rs557211301) and ClinVar (classified as benign by Invitae and as uncertain significance by Illumina). The variant was identified in control databases in 120 of 282576 chromosomes (1 homozygous) at a frequency of 0.0004247, and was observed at the highest frequency in the South Asian population in 113 of 30610 chromosomes (freq: 0.003692) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.A3742 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome and Splice AI genome) do not predict a deleterious effect on splicing. 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.	RCV000463053	SCV002075490	likely benign	Autosomal recessive polycystic kidney disease	2018-04-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003932735	SCV004751905	likely benign	PKHD1-related disorder	2022-02-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).