1-23808187-T-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000191.3(HMGCL):c.698A>G(p.His233Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H233H) has been classified as Likely benign.
Frequency
Consequence
NM_000191.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMGCL | NM_000191.3 | c.698A>G | p.His233Arg | missense_variant | 7/9 | ENST00000374490.8 | |
HMGCL | NM_001166059.2 | c.485A>G | p.His162Arg | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMGCL | ENST00000374490.8 | c.698A>G | p.His233Arg | missense_variant | 7/9 | 1 | NM_000191.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152108Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251412Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135876
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727208
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152108Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 23, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2022 | 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) - |
HMGCL-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 15, 2023 | 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. - |
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 14, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at