The HMGCL c.698A>G variant is predicted to result in the amino acid substitution p.His233Arg. This variant has previously been reported to be causative for HMG-CoA lyase deficiency (Pospísilová E et al 2003. PubMed ID: 14518825; Mitchell GA et al 1998. PubMed ID: 9463337; Menao S et al 2009. PubMed ID: 19177531). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24134677-T-C). This variant is interpreted as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000191.3(HMGCL):c.698A>G (p.His233Arg)
Germline
Classification
Help
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.
(10)
Help
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000191.3(HMGCL):c.698A>G (p.His233Arg)
Variation ID: 167180 Accession: VCV000167180.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.11 1: 23808187 (GRCh38) [ NCBI UCSC ] 1: 24134677 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 29, 2015 Jun 17, 2024 Mar 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000191.3:c.698A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000182.2:p.His233Arg missense NM_001166059.2:c.485A>G NP_001159531.1:p.His162Arg missense NC_000001.11:g.23808187T>C NC_000001.10:g.24134677T>C NG_013061.1:g.22273A>G P35914:p.His233Arg - Protein change
- H233R, H162R
- Other names
- -
- Canonical SPDI
- NC_000001.11:23808186:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| HMGCL | - | - |
GRCh38 GRCh37 |
510 | 528 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 19, 2022 | RCV000153365.16 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 4, 2024 | RCV000665316.22 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 14, 2020 | RCV001831955.9 | |
|
HMGCL-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 15, 2023 | RCV003415999.5 |
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. |
|
|---|---|---|---|---|---|
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Pathogenic
(Jan 23, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000202849.7
First in ClinVar: Feb 02, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Mar 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
HMGCL-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117516.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The HMGCL c.698A>G variant is predicted to result in the amino acid substitution p.His233Arg. This variant has previously been reported to be causative for HMG-CoA … (more)
The HMGCL c.698A>G variant is predicted to result in the amino acid substitution p.His233Arg. This variant has previously been reported to be causative for HMG-CoA lyase deficiency (Pospísilová E et al 2003. PubMed ID: 14518825; Mitchell GA et al 1998. PubMed ID: 9463337; Menao S et al 2009. PubMed ID: 19177531). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24134677-T-C). This variant is interpreted as pathogenic. (less)
|
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004173950.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
|
|
Pathogenic
(Mar 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004199886.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Likely pathogenic
(Feb 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000789416.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893291.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jan 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919521.1
First in ClinVar: May 31, 2019 Last updated: May 31, 2019 |
Comment:
Variant summary: The HMGCL c.698A>G (p.His233Arg) variant involves the alteration of a conserved nucleotide that is located in the Pyruvate carboxyltransferase (InterPro) and is found … (more)
Variant summary: The HMGCL c.698A>G (p.His233Arg) variant involves the alteration of a conserved nucleotide that is located in the Pyruvate carboxyltransferase (InterPro) and is found in the active site required for Mg2+ binding (Fu_2006). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/277164 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic HMGCL variant (0.0007071). The variant is reported in the literature as a homozygous and compound heterozygous allele in multiple patients, and functional studies show undetectable enzyme activity in the fibroblasts and lymphocytes of patients (Roberts_1996, Pospisilova_2003). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002504205.2
First in ClinVar: Apr 30, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant is associated with less than 1% 3-hydroxy-3-methylglutaryl-CoA lyase activity compared to wild-type (Roberts et al., 1996); This variant is associated with the following publications: (PMID: 19177531, 16330550, 9784232, 14518825, 17692550, 15308132, 22847177, 9463337, 8798725) (less)
|
|
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Pathogenic
(Oct 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000818257.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 233 of the HMGCL protein (p.His233Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 233 of the HMGCL protein (p.His233Arg). This variant is present in population databases (rs727503963, gnomAD 0.002%). This missense change has been observed in individual(s) with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (PMID: 9784232, 14518825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167180). 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 HMGCL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMGCL function (PMID: 8798725, 16330550). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 14, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002094155.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
Variant summary: The HMGCL c.698A>G (p.His233Arg) variant involves the alteration of a conserved nucleotide that is located in the Pyruvate carboxyltransferase (InterPro) and is found in the active site required for Mg2+ binding (Fu_2006). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/277164 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic HMGCL variant (0.0007071). The variant is reported in the literature as a homozygous and compound heterozygous allele in multiple patients, and functional studies show undetectable enzyme activity in the fibroblasts and lymphocytes of patients (Roberts_1996, Pospisilova_2003). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant is associated with less than 1% 3-hydroxy-3-methylglutaryl-CoA lyase activity compared to wild-type (Roberts et al., 1996); This variant is associated with the following publications: (PMID: 19177531, 16330550, 9784232, 14518825, 17692550, 15308132, 22847177, 9463337, 8798725)
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 233 of the HMGCL protein (p.His233Arg). This variant is present in population databases (rs727503963, gnomAD 0.002%). This missense change has been observed in individual(s) with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (PMID: 9784232, 14518825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167180). 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 HMGCL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMGCL function (PMID: 8798725, 16330550). 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:
The HMGCL c.698A>G variant is predicted to result in the amino acid substitution p.His233Arg. This variant has previously been reported to be causative for HMG-CoA lyase deficiency (Pospísilová E et al 2003. PubMed ID: 14518825; Mitchell GA et al 1998. PubMed ID: 9463337; Menao S et al 2009. PubMed ID: 19177531). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24134677-T-C). This variant is interpreted as pathogenic.
Comment:
Variant summary: The HMGCL c.698A>G (p.His233Arg) variant involves the alteration of a conserved nucleotide that is located in the Pyruvate carboxyltransferase (InterPro) and is found in the active site required for Mg2+ binding (Fu_2006). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/277164 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic HMGCL variant (0.0007071). The variant is reported in the literature as a homozygous and compound heterozygous allele in multiple patients, and functional studies show undetectable enzyme activity in the fibroblasts and lymphocytes of patients (Roberts_1996, Pospisilova_2003). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant is associated with less than 1% 3-hydroxy-3-methylglutaryl-CoA lyase activity compared to wild-type (Roberts et al., 1996); This variant is associated with the following publications: (PMID: 19177531, 16330550, 9784232, 14518825, 17692550, 15308132, 22847177, 9463337, 8798725)
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 233 of the HMGCL protein (p.His233Arg). This variant is present in population databases (rs727503963, gnomAD 0.002%). This missense change has been observed in individual(s) with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (PMID: 9784232, 14518825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167180). 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 HMGCL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMGCL function (PMID: 8798725, 16330550). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria. | Menao S | Human mutation | 2009 | PMID: 19177531 |
| Molecular genetics of HMG-CoA lyase deficiency. | Pié J | Molecular genetics and metabolism | 2007 | PMID: 17692550 |
| Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria. | Fu Z | The Journal of biological chemistry | 2006 | PMID: 16330550 |
| The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. | Cardoso ML | Molecular genetics and metabolism | 2004 | PMID: 15308132 |
| Biochemical and molecular analyses in three patients with 3-hydroxy-3-methylglutaric aciduria. | Pospísilová E | Journal of inherited metabolic disease | 2003 | PMID: 14518825 |
| Two missense point mutations in different alleles in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene produce 3-hydroxy-3-methylglutaric aciduria in a French patient. | Zapater N | Archives of biochemistry and biophysics | 1998 | PMID: 9784232 |
| HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. | Mitchell GA | American journal of human genetics | 1998 | PMID: 9463337 |
| A nonsense mutation in the exon 2 of the 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL) gene producing three mature mRNAs is the main cause of 3-hydroxy-3-methylglutaric aciduria in European Mediterranean patients. | Casale CH | Archives of biochemistry and biophysics | 1998 | PMID: 9439591 |
| Modeling of a mutation responsible for human 3-hydroxy-3-methylglutaryl-CoA lyase deficiency implicates histidine 233 as an active site residue. | Roberts JR | The Journal of biological chemistry | 1996 | PMID: 8798725 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HMGCL | - | - | - | - |
Text-mined citations for rs727503963 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.