Submissions for variant NM_138694.4(PKHD1):c.7921A>G (p.Thr2641Ala)

gnomAD frequency: 0.00773  dbSNP: rs7766366

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082576	SCV000114618	benign	not specified	2013-09-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000169040	SCV000220198	likely benign	Autosomal recessive polycystic kidney disease	2014-03-27	criteria provided, single submitter	literature only
Invitae	RCV000169040	SCV000260340	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000082576	SCV000297372	likely benign	not specified	2015-10-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082576	SCV000315834	benign	not specified		criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000169040	SCV000803474	benign	Autosomal recessive polycystic kidney disease	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Illumina Laboratory Services, Illumina	RCV000169040	SCV001327302	benign	Autosomal recessive polycystic kidney disease	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082576	SCV001519480	benign	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.7921A>G (p.Thr2641Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251222 control chromosomes, predominantly at a frequency of 0.025 within the African or African-American subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.5- fold the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.7921A>G has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Furu_2003, Melchionda_2016), but also in controls (e.g. Sharp_2005). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001705802	SCV001845304	benign	not provided	2021-03-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12874454, 20981092)
CeGaT Center for Human Genetics Tuebingen	RCV001705802	SCV004185358	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PKHD1: BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292310	SCV001481075	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Thr2641Ala variant was identified in 2 of 320 proband chromosomes (frequency: 0.01) from individuals or families with ARPKD and was present in 2 of 200 control chromosomes (frequency: 0.01) from healthy individuals (Furu 2003, Sharp 2005). The variant was also identified in dbSNP (ID: rs7766366) as With other allele, ClinVar (classified as benign by Invitae, Prevention Genetcs, EGL; as likely benign by Counsyl and one clinical laboratory), Clinvitae, LOVD 3.0 (likely pathogenic), RWTH AAachen University ARPKD database (pathogenic), databases. The variant was not identified in GeneInsight-COGR, databases. The variant was identified in control databases in 715 of 276948 chromosomes (14 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 597 of 24022 chromosomes (freq: 0.02), Other in 16 of 6466 chromosomes (freq: 0.002), Latino in 73 of 34392 chromosomes (freq: 0.002), European in 28 of 126528 chromosomes (freq: 0.0002), and South Asian in 1 of 30778 chromosomes (freq: 0.000032), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, populations. The p.Thr2641 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Natera, Inc.	RCV000169040	SCV002078004	likely benign	Autosomal recessive polycystic kidney disease	2017-06-30	no assertion criteria provided	clinical testing