Submissions for variant NM_138694.4(PKHD1):c.10957A>G (p.Met3653Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002958689	SCV003278467	uncertain significance	Autosomal recessive polycystic kidney disease	2021-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 3653 of the PKHD1 protein (p.Met3653Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs373185996, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003943636	SCV004760400	uncertain significance	PKHD1-related disorder	2023-12-07	criteria provided, single submitter	clinical testing	The PKHD1 c.10957A>G variant is predicted to result in the amino acid substitution p.Met3653Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51523967-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.