Submissions for variant NM_138694.4(PKHD1):c.11509G>A (p.Val3837Ile)

gnomAD frequency: 0.04948  dbSNP: rs9474034

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082520	SCV000114562	benign	not specified	2012-07-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082520	SCV000315762	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000281642	SCV000464025	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000281642	SCV000557650	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001705788	SCV001890306	benign	not provided	2018-07-14	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292049	SCV001480691	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Val3837Ile variant was not identified in the literature nor was it identified in the GeneInsight-COGR, LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs9474034) as With other allele, ClinVar (classified as benign by Initae, EGL Diagnistics; classified as likely benign by illumina), Clinvitae, RWTH AAachen University ARPKD database, databases. The variant was identified in control databases in 4161 of 276500 chromosomes (281 homozygous) at a frequency of 0.02 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 3772 of 24000 chromosomes (freq: 0.2), Other in 47 of 6438 chromosomes (freq: 0.01), Latino in 264 of 34314 chromosomes (freq: 0.01), EuropeanNon-Finnish in 64 of 126248 chromosomes (freq: 0.001), and SouthAsian in 14 of 30766 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Val3837= 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 p.Val3837Ile variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in 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.	RCV000281642	SCV002075477	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing