Submissions for variant NM_138694.4(PKHD1):c.11747C>G (p.Ser3916Ter)

dbSNP: rs760426769

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000733087	SCV000861106	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004184	SCV001163009	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485925	SCV002785885	likely pathogenic	Polycystic kidney disease 4	2021-10-20	criteria provided, single submitter	clinical testing
Invitae	RCV001004184	SCV002938000	pathogenic	Autosomal recessive polycystic kidney disease	2022-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PKHD1 protein in which other variant(s) (p.Arg3961*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 597072). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. This variant is present in population databases (rs760426769, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Ser3916*) in the PKHD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 159 amino acid(s) of the PKHD1 protein.
Baylor Genetics	RCV002485925	SCV004202280	likely pathogenic	Polycystic kidney disease 4	2023-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892657	SCV004717932	likely pathogenic	PKHD1-related disorder	2024-02-23	criteria provided, single submitter	clinical testing	The PKHD1 c.11747C>G variant is predicted to result in premature protein termination (p.Ser3916*). To our knowledge, this variant has not been reported in the literature. This variant is located within the last 50 base pairs of the penultimate exon (66 of 67) of the PKHD1 gene. However, a more downstream (3') nonsense variant in this gene, defined as c.11881C>T (p.Arg3961*), has been reported in two siblings with autosomal recessive polycystic kidney disease (ARPKD) as in trans with a pathogenic variant c.11611T>C (p.Trp3871Arg) and this 3' end nonsense variant is likely pathogenic as the second causative allele for ARPKD in this family (Ishiko et al. 2021. PubMed ID: 34536170). The c.11747C>G (p.Ser3916*) variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD. In summary, this variant is interpreted as likely pathogenic.