Submissions for variant NM_138694.4(PKHD1):c.8521A>G (p.Met2841Val)

gnomAD frequency: 0.00702  dbSNP: rs113562492

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169052	SCV000220212	likely benign	Autosomal recessive polycystic kidney disease	2014-04-09	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000179159	SCV000231360	benign	not specified	2014-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169052	SCV000291342	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000179159	SCV000540040	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 119/13004=0.91%; Frequency in ESP (AA): 103/4303=2.39%
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179159	SCV000918000	benign	not specified	2018-01-30	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8521A>G (p.Met2841Val) located in the G8 domain (via InterPro) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant allele was found at a frequency of 0.0031 in 275668 control chromosomes, predominantly at a frequency of 0.021 within the African subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 3-fold higher than 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 origin. Multiple publications have cited the variant in affected individuals, however, with limited information, i.e. lack of co-occurrence and/or cosegregation data. One publication reports the variant in a compound heterozygote patient, Met2841V/p.Tyr938fs, without providing cosegregation data (Losekoot_2005). Multiple clinical diagnostic laboratories have cited the variant with a classification of "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000169052	SCV001323393	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001527869	SCV001739012	benign	not provided	2020-03-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22995991, 27884173, 15805161)
CeGaT Center for Human Genetics Tuebingen	RCV001527869	SCV004163593	benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292233	SCV001481064	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Met2841Val variant was identified in 2 of 228 proband chromosomes (frequency: 0.009) from individuals or unrelated families with ARPKD (Losekoot 2005, Sharp 2005). The variant was also identified in the following databases: dbSNP (ID: rs113562492) as “With other allele”, ClinVar (4x, as benign by EGL Genetics, Invitae and likely benign by Counsyl, and Laboratory for Molecular Medicine), LOVD 3.0 (1x, reported "does not affect function") and RWTH AAachen University ARPKD database (1x). The variant was identified in control databases in 856 of 275468 (12 homozygous) chromosomes at a frequency of 0.003 in the following populations: African in 497 (10 homozygous) of 23972 chromosomes (freq. 0.02), other in 17 of 6418 chromosomes (freq. 0.0026), Latino in 37 of 3490 chromosomes (freq. 0.001), European in 49 of 125822 chromosomes (freq. 0.0004), Ashkenazi Jewish in 254 of 10128 chromosomes (freq. 0.025), South Asian in 2 of 30750 chromosomes (freq. 0.000065), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Met2841Val 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; this is not very predictive of pathogenicity. The variant is located with the G8 domain functional domain(s) increasing the likelihood that it may have clinical significance. In addition the p.Met2841Val variant was identified in trans with the PKHD1 (c.2812_2813del, p.Tyr938fs) mutation (Losekoot 2005). In summary, based on the above information this variant meets our laboratory criteria to be classified as benign.
Natera, Inc.	RCV000169052	SCV002077977	benign	Autosomal recessive polycystic kidney disease	2020-04-08	no assertion criteria provided	clinical testing