Submissions for variant NM_138694.4(PKHD1):c.5134G>A (p.Gly1712Arg)

gnomAD frequency: 0.00056  dbSNP: rs141103838

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000414198	SCV000340175	uncertain significance	not provided	2018-04-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000373143	SCV000487187	likely pathogenic	Autosomal recessive polycystic kidney disease	2016-10-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000414198	SCV000490722	likely pathogenic	not provided	2016-09-28	criteria provided, single submitter	clinical testing	The G1712R variant in the PKHD1 gene has been reported previously, along with a second mutation, in an individual with ARPKD (Gunay-Aygun et al., 2010). Although not present in the homozygous state, the NHLBI Exome Sequencing Project reports G1712R was observed in 14/8600 alleles from individuals of European background, indicating it may be a rare variant in this population. The G1712R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G1712R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV000373143	SCV000545846	likely benign	Autosomal recessive polycystic kidney disease	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000373143	SCV000915336	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	The PKHD1 c.5134G>A (p.Gly1712Arg) variant has been reported in three studies in which it is found in a compound heterozygous state with a frameshift variant in one individual with polycystic kidney disease (Gunay-Aygun et al. 2010). The p.Gly1712Arg variant was absent from 400 control chromosomes and is reported at a frequency of 0.00163 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. Therefore, the p.Gly1712Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000373143	SCV001362923	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-04-13	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5134G>A (p.Gly1712Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 251314 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00074 vs 0.0071), allowing no conclusion about variant significance. c.5134G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Gunay-Aygun_2010, Denamur_2010, Bullich_2018, Schueler_2016, Baldridge_2017, Mallawaarachchi_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, six classified the variant as uncertain significance, and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000414198	SCV001422396	uncertain significance	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000414198	SCV001714173	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001580479	SCV001810569	uncertain significance	Polycystic kidney disease 4	2021-07-22	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001580479	SCV001984628	uncertain significance	Polycystic kidney disease 4	2020-08-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003391047	SCV004119422	likely pathogenic	PKHD1-related condition	2023-12-01	criteria provided, single submitter	clinical testing	The PKHD1 c.5134G>A variant is predicted to result in the amino acid substitution p.Gly1712Arg. Along with a pathogenic frameshift PKHD1 variant, the c.5134G>A (p.Gly1712Arg) variant has been reported in a patient with polycystic kidney disease (PKD) diagnosed at 28 years of age (Gunay-Aygun et al. PubMed ID: 19914852; Gunay-Aygun et al. PubMed ID: 20413436). This variant was also described in several other patients with polycystic kidney disease; these patients each harbored a known or potentially causative second variant in PKHD1 (Bullich et al. 2018. PubMed ID: 29801666, Supplementary Table 1; Schueler et al. 2016. PubMed ID: 26673778, Supplementary Table 2; Denamur et al. 2010. PubMed ID: 19940839, Table S2) and this variant has been identified in at least one ARPKD (autosomal recessive polycystic kidney disease) patient with a second PKHD1 variant at PreventionGenetics. This variant is reported in 0.48% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV001580479	SCV004204029	likely pathogenic	Polycystic kidney disease 4	2023-10-31	criteria provided, single submitter	clinical testing