Submissions for variant NM_138694.4(PKHD1):c.10637del (p.Val3546fs)

gnomAD frequency: 0.00003  dbSNP: rs770461067

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000308290	SCV000329470	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12506140, 31589614, 15805161, 19914852, 19940839, 27752906, 11919560)
Eurofins Ntd Llc (ga)	RCV000308290	SCV000702100	pathogenic	not provided	2018-06-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780594	SCV000917994	pathogenic	Autosomal recessive polycystic kidney disease	2017-10-30	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.10637delT (p.Val3546AlafsX22) variant results in a premature termination codon, predicted to cause a truncated or absent PKHD1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.11314C>T (p.Arg3772X) has been classified as pathogenic by our laboratory. This variant was found in 3/244940 control chromosomes (gnomAD) at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Multiple publications have cited this variant in affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000780594	SCV001163013	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Invitae	RCV000780594	SCV001231583	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val3546Alafs*22) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is present in population databases (rs770461067, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 11919560, 19940839, 27752906). ClinVar contains an entry for this variant (Variation ID: 279874). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001782763	SCV002018822	pathogenic	Polycystic kidney disease 4	2019-10-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001782763	SCV002777879	pathogenic	Polycystic kidney disease 4	2022-04-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000308290	SCV002821376	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	PKHD1: PVS1, PM2
Baylor Genetics	RCV001782763	SCV004202206	pathogenic	Polycystic kidney disease 4	2023-10-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV003985310	SCV004801714	pathogenic	See cases	2024-02-04	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PP4,PP5
Natera, Inc.	RCV000780594	SCV002075505	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-16	no assertion criteria provided	clinical testing