Submissions for variant NM_138694.4(PKHD1):c.6211A>C (p.Asn2071His)

gnomAD frequency: 0.00271  dbSNP: rs143832120

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000247246	SCV000315818	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000247246	SCV000702217	benign	not specified	2016-09-26	criteria provided, single submitter	clinical testing
Invitae	RCV000861148	SCV001001381	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000247246	SCV001448409	likely benign	not specified	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.6211A>C (p.Asn2071His) 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. The variant allele was found at a frequency of 0.0014 in 282594 control chromosomes, predominantly at a frequency of 0.0093 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.32 fold of 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. To our knowledge, no occurrence of c.6211A>C in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001553091	SCV001773897	likely benign	not provided	2020-11-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292311	SCV001481076	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Asn2071His variant was not identified in the literature nor was it identified in the LOVD 3.0, RWTH AAachen University ARPKD databases. The variant was identified in dbSNP (ID: rs143832120) as “With Likely benign allele”, ClinVar (as likely benign by Prevention Genetics), and Clinvitae (1x as likely benign). The variant was also identified in control databases in 380 of 276894 chromosomes at a frequency of 0.001372 in the following populations: African in 212 (2 homozygous) of 24024 chromosomes (freq. 0.0088), Ashkenazi Jewish in 46 of 10144 chromosomes (freq. 0.0045), South Asian in 78 (2 homozyogous) of 30782 chromsomes (freq. 0.0025), Other in 9 of 34354 chromosomes (freq. 0.0014), Latino in 20 of 34354 chromosomes (freq. 0.0006), and European (Non-Finnish) in 15 of 126500 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asn2071 residue is not conserved in mammals and the variant amino acid histidine (His) is present in many species including chimpanzees, macaques, dogs, and horses, increasing the likelihood that this variant does not have clinical significance. In addition, 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as likely benign.
Natera, Inc.	RCV000861148	SCV002078056	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing