rs777849213
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong
The NM_001358263.1(HK1):c.2551G>A(p.Glu851Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
HK1
NM_001358263.1 missense
NM_001358263.1 missense
Scores
6
4
2
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
HK1 (HGNC:4922): (hexokinase 1) Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in several transcript variants which encode different isoforms, some of which are tissue-specific. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, HK1
PP5
?
Variant 10-69398758-G-A is Pathogenic according to our data. Variant chr10-69398758-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-69398758-G-A is described in Lovd as [Pathogenic]. Variant chr10-69398758-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HK1 | NM_001358263.1 | c.2551G>A | p.Glu851Lys | missense_variant | 20/21 | ENST00000643399.2 | |
HK1 | NM_000188.3 | c.2539G>A | p.Glu847Lys | missense_variant | 17/18 | ENST00000359426.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HK1 | ENST00000643399.2 | c.2551G>A | p.Glu851Lys | missense_variant | 20/21 | NM_001358263.1 | |||
HK1 | ENST00000359426.7 | c.2539G>A | p.Glu847Lys | missense_variant | 17/18 | 1 | NM_000188.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251396Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135866
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727242
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 79 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 27, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Glu851Lys variant in HK1 was identified by our study in two siblings and their parent, all with Retinitis Pigmentosa. This variant has been identified in 0.001219% (3/246124) of chromosomes and by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs777849213). Please note that for diseases like Retinitis Pigmentosa with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, its frequency is low enough to be consistent with the frequency of a disease with incomplete penetrance. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 424845). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional computational prediction tools suggest a missense variant in the HK1 gene may not be tolerated. The p.Glu851Lys variant in HK1 has been reported in 43 Caucasian, American, Asian, French Canadian, and Sicilian individuals with Retinitis Pigmentosa and segregated with disease in 38 affected relatives from 10 families (PMID: 25316723, 25190649, 26427411, 28765615). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP2, PP3, PP1_Strong (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 07, 2022 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 847 of the HK1 protein (p.Glu847Lys). This variant is present in population databases (rs777849213, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 25190649, 25316723, 28765615). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Glu851Lys. ClinVar contains an entry for this variant (Variation ID: 424845). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HK1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HK1 function (PMID: 25316723). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 27, 2021 | - - |
Retinal dystrophy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 25, 2019 | - - |
Retinal atrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Aug 27, 2021 | ACMG categories: PS3,PM1,PM2,PP3,PP4 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
D;D;B;D;D;P
Vest4
0.94, 0.92, 0.94, 0.92
MVP
0.86
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at