NM_001358263.1:c.2551G>A

Variant names:

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 10.0

Variant links:

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]

HK1 links:

Genome browser will be placed here

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 in the HK1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Trascript score misZ: 5.1108 (above the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa 79, non-spherocytic hemolytic anemia due to hexokinase deficiency, neurodevelopmental disorder with visual defects and brain anomalies, Charcot-Marie-Tooth disease type 4G.

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 rank	MANE	Protein	UniProt
HK1	NM_001358263.1 link	c.2551G>A	p.Glu851Lys	missense_variant	Exon 20 of 21	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3 link	c.2539G>A	p.Glu847Lys	missense_variant	Exon 17 of 18	ENST00000359426.7	NP_000179.2	P19367-1B3KXY9A8K7J7Q59FD4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2 link	c.2551G>A	p.Glu851Lys	missense_variant	Exon 20 of 21		NM_001358263.1	ENSP00000494664.1		P19367-3
HK1	ENST00000359426.7 link	c.2539G>A	p.Glu847Lys	missense_variant	Exon 17 of 18	1	NM_000188.3	ENSP00000352398.6		P19367-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251396

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 79

Pathogenic:4

Apr 27, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

REVEL score is 0.819 (PP3_mod). Variant is not found in gnomAD genomes (PM2). Cosegregation observed in multiple families in multiple studies (PP1_str, PMID:25316723;25190649;28765615) -

Feb 07, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Apr 27, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence 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 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. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:3

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

See cases

Pathogenic:1

Aug 27, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS3,PM1,PM2,PP3,PP4 -

HK1-related disorder

Pathogenic:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HK1 c.2539G>A variant is predicted to result in the amino acid substitution p.Glu847Lys. This variant (also described as p.Glu851Lys and p.Glu882Lys in alternate transcripts) has been reported and shown to co-segregate with disease in multiple individuals and families with autosomal dominant retinitis pigmentosa 79 (RP79) and related phenotypes (Sullivan et al. 2014. PubMed ID: 25190649; Wang et al. 2014. PubMed ID: 25316723; Yuan et al. 2017. PubMed ID: 28765615; Kubota et al. 2020. PubMed ID: 32814480; Table S2, Suga et al. 2022. PubMed ID: 36284460; Table S4, Panneman et al. 2023. PubMed ID: 36819107). This variant was also reported in the homozygous state in a severely affected individual (Sullivan et al. 2014. PubMed ID: 25190649), and incomplete penetrance (~85%) has been noted in at least one family (Wang et al. 2014. PubMed ID: 25316723). One functional study showed that this variant does not affect hexokinase enzymatic activity or protein stability (Wang et al. 2014. PubMed ID: 25316723). However, these results should be considered inconclusive at this time, since it remains unresolved whether p.Glu847Lys pathogenicity is due to mechanism other than HK1 haploinsufficiency (e.g., a dominant-negative or gain-of-function effect). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as pathogenic and likely pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/424845/). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

.;.;.;.;.;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;D;D;.;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.65

D;D;D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.5

.;.;.;.;.;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.4

.;.;N;.;N;N

REVEL

Pathogenic

0.82

Sift

Benign

0.060

.;.;T;.;T;T

Sift4G

Benign

0.15

.;T;T;.;T;T

Polyphen

0.98

D;D;B;D;D;P

Vest4

0.94, 0.92, 0.94, 0.92

MVP

0.86

ClinPred

0.59

GERP RS

4.6

Varity_R

0.56

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over