rs372340268
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_138694.4(PKHD1):c.934C>T(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,604,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312Q) has been classified as Likely benign.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.934C>T | p.Arg312Trp | missense_variant | 13/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.934C>T | p.Arg312Trp | missense_variant | 13/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.934C>T | p.Arg312Trp | missense_variant | 13/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000944 AC: 14AN: 148348Hom.: 0 Cov.: 23
GnomAD3 exomes AF: 0.000124 AC: 31AN: 250844Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135574
GnomAD4 exome AF: 0.000136 AC: 198AN: 1455784Hom.: 0 Cov.: 30 AF XY: 0.000139 AC XY: 101AN XY: 724414
GnomAD4 genome ? AF: 0.0000944 AC: 14AN: 148348Hom.: 0 Cov.: 23 AF XY: 0.0000831 AC XY: 6AN XY: 72174
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2021 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the PKHD1 protein (p.Arg312Trp). This variant is present in population databases (rs372340268, gnomAD 0.06%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 33123899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 502343). 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 not expected to disrupt PKHD1 protein function. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 16, 2017 | - - |
Polycystic kidney disease Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Arg312Trp variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or the RWTH AAachen University ARPKD database. The identification of this variant in one individual by our laboratory with ARPKD and a co-occurring pathogenic variant in ARPKD, increases the likelihood, this variant may have clinical significance. The variant was identified in dbSNP (ID: rs372340268) as “NA”, and in control databases in 33 of 275364 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 2 of 23724 chromosomes (freq: 0.00008), European Non-Finnish in 11 of 125766 chromosomes (freq: 0.00009), and South Asian in 20 of 30782 chromosomes (freq: 0.0007) and was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Arg312 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 29, 2018 | - - |
PKHD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 02, 2024 | The PKHD1 c.934C>T variant is predicted to result in the amino acid substitution p.Arg312Trp. This variant was reported with a deletion affecting exons 12-13 of PKHD1 in an individual with hepatic fibrosis and normal renal function (Qiu et al. 2020. PubMed ID: 33123899). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Polycystic kidney disease 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at