rs777849213

Positions:

• chr10-69398758-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HK1. . Trascript score misZ 5.1108 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
HK1	NM_001358263.1	c.2551G>A	p.Glu851Lys	missense_variant	20/21	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3	c.2539G>A	p.Glu847Lys	missense_variant	17/18	ENST00000359426.7	NP_000179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.2551G>A	p.Glu851Lys	missense_variant	20/21		NM_001358263.1	ENSP00000494664
HK1	ENST00000359426.7	c.2539G>A	p.Glu847Lys	missense_variant	17/18	1	NM_000188.3	ENSP00000352398	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251396 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

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: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	- -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 25, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

See cases 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 -

HK1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

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	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;.;.;.;.;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	1.5	.;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
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	D
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

Other links and lift over

dbSNP: rs777849213; hg19: chr10-71158514; COSMIC: COSV53859655;