Submissions for variant NM_138694.4(PKHD1):c.9719G>T (p.Arg3240Leu)

dbSNP: rs146649803

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153706	SCV000203264	uncertain significance	not provided	2014-03-11	criteria provided, single submitter	clinical testing
Invitae	RCV000200664	SCV000253724	pathogenic	Autosomal recessive polycystic kidney disease	2023-09-08	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 167478). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3240 of the PKHD1 protein (p.Arg3240Leu). This variant is present in population databases (rs146649803, gnomAD 0.0009%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 15805161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. This variant disrupts the p.Arg3240 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15698423, 19914852, 20413436, 24162162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780600	SCV000918008	uncertain significance	not specified	2017-12-11	criteria provided, single submitter	clinical testing	Variant summary: The c.9719G>T (pArg3240Leu) in PKHD1 gene is a missense variant involves a conserved nucleotide located outside of any known functional domain or repeat. The 4/4 in silico tools used predict damaging outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.9719G>T was identified in the control population dataset of gnomAD at a low frequency of 0.000004 (1/245990 chrs tested). The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.007, suggesting that it is not a common polymorphism. The variant has been reported in compound heterozygosity in 1 fetal sample with confirmed dx of ARPKD and is cited as VUS/Likely Pathogenic by reputable databases/clinical laboratories. In addition, other alterations of Arg3240 codon have been reported in association with ARPKD. Taken together, the variant was classified as VUS-Possibly Pathogenic, until new information becomes available.
GeneDx	RCV000153706	SCV004034360	likely pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9511976, 15805161)
PreventionGenetics, part of Exact Sciences	RCV003416003	SCV004118449	likely pathogenic	PKHD1-related disorder	2022-12-11	criteria provided, single submitter	clinical testing	The PKHD1 c.9719G>T variant is predicted to result in the amino acid substitution p.Arg3240Leu. This variant was reported along with a second PKHD1 variant in a prenatal case of autosomal recessive polycystic kidney disease (ARPKD) (Sharp et al. 2005. PubMed ID: 15805161). Internally, we have observed this variant in the compound heterozygous state with a second PKHD1 variant in two families with individuals affected with ARPKD. An alternate substitution impacting the same amino acid (p.Arg3240Gln) has also been reported in patients with ARPKD (e.g., Bergmann et al. 2005. PubMed ID: 15698423; https://www.ncbi.nlm.nih.gov/clinvar/variation/572902). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51612695-C-A). Taken together, this variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003474810	SCV004202262	likely pathogenic	Polycystic kidney disease 4	2023-10-04	criteria provided, single submitter	clinical testing