VCV000992937.60 - ClinVar

NM_001358263.1(HK1):c.75+20308C>T

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001358263.1(HK1):c.75+20308C>T

Variation ID: 992937 Accession: VCV000992937.60

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.1 10: 69315988 (GRCh38) [ NCBI UCSC ] 10: 71075744 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 18, 2021	Oct 20, 2024	Mar 21, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001358263.1:c.75+20308C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001322364.2:c.75+20308C>T		intron variant
NM_001322365.2:c.168+20308C>T		intron variant
NM_033496.3:c.34C>T	NP_277031.1:p.Arg12Ter	nonsense
NM_033497.3:c.75+20308C>T		intron variant
NM_033498.3:c.75+20308C>T		intron variant
NM_033500.2:c.27+15127C>T		intron variant
NC_000010.11:g.69315988C>T
NC_000010.10:g.71075744C>T
NG_012077.1:g.50989C>T
LRG_365:g.50989C>T
LRG_365t1:c.27+15127C>T

... more HGVS ... less HGVS

Protein change

R12*

Other names

Canonical SPDI

NC_000010.11:69315987:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

dbSNP: rs756166032 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HK1		-	-	GRCh38 GRCh37	657	682

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hemolytic anemia due to hexokinase deficiency	Pathogenic (1)	criteria provided, single submitter	Mar 29, 2018	RCV001534610.10
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Mar 21, 2022	RCV001726477.33

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 29, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemolytic anemia due to hexokinase deficiency Affected status: yes Allele origin: germline	UOS Fisiopatologia delle Anemie, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano Accession: SCV001469081.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Number of individuals with the variant: 1
Pathogenic (Mar 21, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003786506.3 First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 31119733‚ 11783948‚ 12211198 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hemolytic anemia (PMID: 31119733). … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hemolytic anemia (PMID: 31119733). This variant is present in population databases (rs756166032, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg12*) in the HK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HK1 are known to be pathogenic (PMID: 11783948, 12211198, 31119733). The HK1 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_033496.2, and corresponds to NM_000188.2:c.-2960C>T in the primary transcript. (less)
Uncertain significance (Aug 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001961225.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hemolytic anemia (PMID: 31119733). This variant is present in population databases (rs756166032, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg12*) in the HK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HK1 are known to be pathogenic (PMID: 11783948, 12211198, 31119733). The HK1 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_033496.2, and corresponds to NM_000188.2:c.-2960C>T in the primary transcript.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A nonsense variant in the Hexokinase 1 gene (HK1) causing severe non-spherocytic haemolytic anaemia: genetic analysis exemplifies ambiguity due to multiple Isoforms.	Jamwal M	British journal of haematology	2019	PMID: 31119733
Homozygous intragenic deletion of type I hexokinase gene causes lethal hemolytic anemia of the affected fetus.	Kanno H	Blood	2002	PMID: 12211198
Downeast anemia (dea), a new mouse model of severe nonspherocytic hemolytic anemia caused by hexokinase (HK(1)) deficiency.	Peters LL	Blood cells, molecules & diseases	2001	PMID: 11783948

Text-mined citations for rs756166032 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 07, 2024

ClinVar Genomic variation as it relates to human health

NM_001358263.1(HK1):c.75+20308C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs756166032 ...