VCV000421007.51 - ClinVar

NM_000188.3(HK1):c.1334C>T (p.Ser445Leu)

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.

(14)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000188.3(HK1):c.1334C>T (p.Ser445Leu)

Variation ID: 421007 Accession: VCV000421007.51

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.1 10: 69382555 (GRCh38) [ NCBI UCSC ] 10: 71142311 (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	Apr 27, 2017	Oct 20, 2024	Jan 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000188.3:c.1334C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000179.2:p.Ser445Leu	missense
NM_001358263.1:c.1346C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001345192.1:p.Ser449Leu	missense
NM_001322364.2:c.1346C>T	NP_001309293.1:p.Ser449Leu	missense
NM_001322365.2:c.1439C>T	NP_001309294.1:p.Ser480Leu	missense
NM_001322366.1:c.1250C>T	NP_001309295.1:p.Ser417Leu	missense
NM_001322367.1:c.1238C>T	NP_001309296.1:p.Ser413Leu	missense
NM_033496.3:c.1331C>T	NP_277031.1:p.Ser444Leu	missense
NM_033497.3:c.1346C>T	NP_277032.1:p.Ser449Leu	missense
NM_033498.3:c.1346C>T	NP_277033.1:p.Ser449Leu	missense
NM_033500.2(HK1):c.1298C>T		missense
NM_033500.2:c.1298C>T	NP_277035.2:p.Ser433Leu	missense
NC_000010.11:g.69382555C>T
NC_000010.10:g.71142311C>T
NG_012077.1:g.117556C>T
LRG_365:g.117556C>T
LRG_365t1:c.1298C>T	LRG_365p1:p.Ser433Leu

... more HGVS ... less HGVS

Protein change

S433L, S445L, S413L, S417L, S480L, S444L, S449L

Other names

Canonical SPDI

NC_000010.11:69382554: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.

Links

ClinGen: CA16618972 OMIM: 142600.0008 dbSNP: rs1064794848 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.
not provided	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 21, 2024	RCV000483739.35
Neurodevelopmental disorder with visual defects and brain anomalies	Pathogenic (2)	criteria provided, single submitter	Feb 23, 2023	RCV000850128.4
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Sep 13, 2019	RCV001266687.4
Hemolytic anemia due to hexokinase deficiency	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV001770372.4
Retinitis pigmentosa	Likely pathogenic (1)	criteria provided, single submitter	-	RCV001270352.3
Retinitis pigmentosa 79	Pathogenic (1)	criteria provided, single submitter	May 28, 2020	RCV001254702.4
Autism spectrum disorder	Pathogenic (1)	criteria provided, single submitter	-	RCV003126749.3

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 (May 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 79 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001430769.1 First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020	Publications: PubMed (1) PubMed: 30778173 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/56f597e4-216d-4aed-98ef-39cf80bbeed3 Comment: The heterozygous p.Ser445Leu variant in HK1 was identified by our study in an individual with neurodevelopmental disorder with visual defects and brain anomalies (PMID: 30778173). … (more) The heterozygous p.Ser445Leu variant in HK1 was identified by our study in an individual with neurodevelopmental disorder with visual defects and brain anomalies (PMID: 30778173). Trio exome analysis showed this variant to be de novo, and it was absent from large population studies. This variant has been reported pathogenic by GeneDx and OMIM in ClinVar (Variation ID: 421007). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS2, PM2, PP3, PS4_supporting (Richards 2015). (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa Affected status: yes Allele origin: de novo	Department of Genetics, Fundacion Jimenez Diaz University Hospital Accession: SCV001450578.1 First in ClinVar: Dec 16, 2020 Last updated: Dec 16, 2020	Comment: Variant not found in population databases, predicted deleterious by in-silico pathogenicity predictors, reported as pathogenic in ClinVar (VCV000421007.7) , and found to be a de … (more) Variant not found in population databases, predicted deleterious by in-silico pathogenicity predictors, reported as pathogenic in ClinVar (VCV000421007.7) , and found to be a de novo variant. (ACMG: PM2 Moderate; PM6: Moderate; PP3 Supporting; PP5: Supporting) (less)
Likely pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762067.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021	Clinical Features: Rod-cone dystrophy (present) , Cone-rod dystrophy (present) Sex: male
Likely pathogenic (Jun 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501320.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (1) PubMed: 30778173 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Hemolytic anemia due to hexokinase deficiency Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516543.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Likely pathogenic (Sep 13, 2019)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444864.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (1) PubMed: 30778173 Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Cerebral palsy (present) , Febrile seizures (present) , Abnormality of the corpus callosum (present) , Ventriculomegaly (present) , Short stature … (more) Global developmental delay (present) , Cerebral palsy (present) , Febrile seizures (present) , Abnormality of the corpus callosum (present) , Ventriculomegaly (present) , Short stature (present) , Failure to thrive (present) , Hearing impairment (present) , Pigmentary retinopathy (present) , Left ventricular noncompaction cardiomyopathy (present) , Abnormal morphology of the left ventricle (present) , Pulmonary arterial hypertension (present) , Asthma (present) , Cryptorchidism (present) , Premature birth (present) , Maternal teratogenic exposure (present) (less) Sex: male
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autism spectrum disorder Affected status: yes Allele origin: de novo	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV003803847.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Sex: male
Pathogenic (Jan 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000570071.6 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30778173, 34866404, 31785789) (less)
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with visual defects and brain anomalies Affected status: yes Allele origin: unknown	3billion Accession: SCV003841404.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 30778173 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.81). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000421007). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Mitochondrial encephalopathy (present) , Neurodevelopmental delay (present) , Abnormal cerebral white matter morphology (present)
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011166.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Jan 21, 2024)	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: SCV001580959.5 First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30778173 Comment: This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 445 of the HK1 protein (p.Ser445Leu). … (more) This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 445 of the HK1 protein (p.Ser445Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa and neurodevelopmental abnormalities (PMID: 30778173). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421007). 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) performed at Invitae indicates that this missense variant is expected to disrupt HK1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HK1 function (PMID: 30778173). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2020)	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: SCV001334615.25 First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Aug 22, 2019)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH VISUAL DEFECTS AND BRAIN ANOMALIES Affected status: not provided Allele origin: germline	OMIM Accession: SCV000992292.1 First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019	Publications: PubMed (1) PubMed: 30778173 Comment on evidence: In 2 unrelated patients (patients 3 and 4) with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified a … (more) In 2 unrelated patients (patients 3 and 4) with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified a de novo heterozygous c.1334C-T transition (c.1334C-T, NM_000188.2) in the HK1 gene, resulting in a ser445-to-leu (S445L) 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. Hexokinase activity in patient red cells derived from 1 of the patients was normal, suggesting a different pathogenic mechanism. Additional functional studies of the variant were not performed. (less)
Pathogenic (Apr 26, 2022)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031294.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)
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Comment:

The heterozygous p.Ser445Leu variant in HK1 was identified by our study in an individual with neurodevelopmental disorder with visual defects and brain anomalies (PMID: 30778173). Trio exome analysis showed this variant to be de novo, and it was absent from large population studies. This variant has been reported pathogenic by GeneDx and OMIM in ClinVar (Variation ID: 421007). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS2, PM2, PP3, PS4_supporting (Richards 2015).

Comment:

Variant not found in population databases, predicted deleterious by in-silico pathogenicity predictors, reported as pathogenic in ClinVar (VCV000421007.7) , and found to be a de novo variant. (ACMG: PM2 Moderate; PM6: Moderate; PP3 Supporting; PP5: Supporting)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30778173, 34866404, 31785789)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.81). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000421007). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 445 of the HK1 protein (p.Ser445Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa and neurodevelopmental abnormalities (PMID: 30778173). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421007). 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) performed at Invitae indicates that this missense variant is expected to disrupt HK1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HK1 function (PMID: 30778173). For these reasons, this variant has been classified as Pathogenic.

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
De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment.	Okur V	European journal of human genetics : EJHG	2019	PMID: 30778173
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/56f597e4-216d-4aed-98ef-39cf80bbeed3	-	-	-	-

Text-mined citations for rs1064794848 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000188.3(HK1):c.1334C>T (p.Ser445Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1064794848 ...