rs137852636
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate
The NM_005518.4(HMGCS2):āc.520T>Cā(p.Phe174Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,688 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 Pathogenic (ā ).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 33)
Exomes š: 0.0000062 ( 0 hom. )
Consequence
HMGCS2
NM_005518.4 missense
NM_005518.4 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 8.76
Genes affected
HMGCS2 (HGNC:5008): (3-hydroxy-3-methylglutaryl-CoA synthase 2) The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are associated with HMG-CoA synthase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005518.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.751
PP5
?
Variant 1-119764211-A-G is Pathogenic according to our data. Variant chr1-119764211-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 9257.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-119764211-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMGCS2 | NM_005518.4 | c.520T>C | p.Phe174Leu | missense_variant | 2/10 | ENST00000369406.8 | |
HMGCS2 | NM_001166107.1 | c.520T>C | p.Phe174Leu | missense_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMGCS2 | ENST00000369406.8 | c.520T>C | p.Phe174Leu | missense_variant | 2/10 | 1 | NM_005518.4 | P1 | |
HMGCS2 | ENST00000544913.2 | c.520T>C | p.Phe174Leu | missense_variant | 2/9 | 2 | |||
HMGCS2 | ENST00000476640.1 | n.416T>C | non_coding_transcript_exon_variant | 1/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000104 AC: 26AN: 251170Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135728
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461508Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727056
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74328
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
3-hydroxy-3-methylglutaryl-CoA synthase deficiency Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | ClinVar contains an entry for this variant (Variation ID: 9257). This missense change has been observed in individual(s) with HMG-CoA synthase-2 deficiency (PMID: 11228257, 23751782, 25511235, 33045405). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs137852636, gnomAD 0.1%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 174 of the HMGCS2 protein (p.Phe174Leu). 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 not expected to disrupt HMGCS2 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HMGCS2 function (PMID: 11228257, 23751782). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MutPred
Loss of catalytic residue at F174 (P = 0.1428);Loss of catalytic residue at F174 (P = 0.1428);
MVP
MPC
ClinPred
T
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at