NM_000188.3(HK1):c.1370C>T (p.Thr457Met) AND Neurodevelopmental disorder with visual defects and brain anomalies

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 20, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000850129.15

Allele description [Variation Report for NM_000188.3(HK1):c.1370C>T (p.Thr457Met)]

NM_000188.3(HK1):c.1370C>T (p.Thr457Met)

Gene:

HK1:hexokinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_000188.3(HK1):c.1370C>T (p.Thr457Met)

HGVS:

NC_000010.11:g.69382591C>T
NG_012077.1:g.117592C>T
NM_000188.3:c.1370C>TMANE SELECT
NM_001322364.2:c.1382C>T
NM_001322365.2:c.1475C>T
NM_001322366.1:c.1286C>T
NM_001322367.1:c.1274C>T
NM_001358263.1:c.1382C>T
NM_033496.3:c.1367C>T
NM_033497.3:c.1382C>T
NM_033498.3:c.1382C>T
NM_033500.2:c.1334C>T
NP_000179.2:p.Thr457Met
NP_000179.2:p.Thr457Met
NP_001309293.1:p.Thr461Met
NP_001309294.1:p.Thr492Met
NP_001309295.1:p.Thr429Met
NP_001309296.1:p.Thr425Met
NP_001345192.1:p.Thr461Met
NP_277031.1:p.Thr456Met
NP_277032.1:p.Thr461Met
NP_277032.1:p.Thr461Met
NP_277033.1:p.Thr461Met
NP_277035.2:p.Thr445Met
LRG_365t1:c.1334C>T
LRG_365:g.117592C>T
LRG_365p1:p.Thr445Met
NC_000010.10:g.71142347C>T
NM_000188.2:c.1370C>T
NM_033497.2:c.1382C>T

Protein change:

T425M; THR457MET

Links:

OMIM: 142600.0009; dbSNP: rs1057517928

NCBI 1000 Genomes Browser:

rs1057517928

Molecular consequence:

NM_000188.3:c.1370C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322364.2:c.1382C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322365.2:c.1475C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322366.1:c.1286C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322367.1:c.1274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001358263.1:c.1382C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033496.3:c.1367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033497.3:c.1382C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033498.3:c.1382C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033500.2:c.1334C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Neurodevelopmental disorder with visual defects and brain anomalies
Identifiers:: MONDO: MONDO:0032807; MedGen: C5231404; OMIM: 618547

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000992293	OMIM	no assertion criteria provided	Pathogenic (Aug 22, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001149802	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Feb 6, 2020)	de novo	clinical testing	Citation Link,
SCV002765138	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 20, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003835364	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment.

Okur V, Cho MT, van Wijk R, van Oirschot B, Picker J, Coury SA, Grange D, Manwaring L, Krantz I, Muraresku CC, Hulick PJ, May H, Pierce E, Place E, Bujakowska K, Telegrafi A, Douglas G, Monaghan KG, Begtrup A, Wilson A, Retterer K, Anyane-Yeboa K, et al.

Eur J Hum Genet. 2019 Jul;27(7):1081-1089. doi: 10.1038/s41431-019-0366-9. Epub 2019 Feb 18.

PubMed [citation]

PMID:: 30778173
PMCID:: PMC6777464

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000992293.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an 8-year-old boy (patient 5) and 2 sibs who died at 1 year of age (patients 6 and 7), with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified a de novo heterozygous c.1370C-T transition (c.1370C-T, NM000188.2) in the HK1 gene, resulting in a thr457-to-met (T457M) substitution at a highly conserved residue in the N-terminal regulatory domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of over 100,000 exomes. The mutation occurred de novo in patient 5; paternal mosaicism in the blood was excluded in the sibs. Functional studies of the variant and studies of patient cells were not performed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001149802.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
2	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV002765138.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV003835364.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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