rs764039230
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The ENST00000374490.8(HMGCL):c.493C>T(p.Arg165Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,422 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165Q) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000374490.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HMGCL | NM_000191.3 | c.493C>T | p.Arg165Trp | missense_variant | 5/9 | ENST00000374490.8 | NP_000182.2 | |
HMGCL | NM_001166059.2 | c.348+2481C>T | intron_variant | NP_001159531.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HMGCL | ENST00000374490.8 | c.493C>T | p.Arg165Trp | missense_variant | 5/9 | 1 | NM_000191.3 | ENSP00000363614 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152042Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251458Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135902
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461380Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 726990
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152042Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74238
ClinVar
Submissions by phenotype
Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 04, 2022 | NM_000191.2(HMGCL):c.493C>T(R165W) is a missense variant classified as a variant of uncertain significance in the context of HMG-CoA lyase deficiency. R165W has been observed in cases with relevant disease (PMID: 28583327). Functional assessments of this variant are not available in the literature. R165W has been observed in population frequency databases (gnomAD: FIN 0.005%). In summary, there is insufficient evidence to classify NM_000191.2(HMGCL):c.493C>T(R165W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 21, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 165 of the HMGCL protein (p.Arg165Trp). This variant is present in population databases (rs764039230, gnomAD 0.004%). This missense change has been observed in individual(s) with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (PMID: 10916782, 28583327). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 558583). 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%. This variant disrupts the p.Arg165 amino acid residue in HMGCL. Other variant(s) that disrupt this residue have been observed in individuals with HMGCL-related conditions (PMID: 19036343, 19932602), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 16, 2020 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2024 | 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: 10916782, 28583327) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at