1-119750827-C-G

Position:

• chr1-119750827-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005518.4(HMGCS2):​c.1502G>C​(p.Arg501Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,590 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R501Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 4) in uniprot entity HMCS2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005518.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-119750827-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3383101.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-119750827-C-G is Pathogenic according to our data. Variant chr1-119750827-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 452101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.1502G>C	p.Arg501Pro	missense_variant	9/10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.1376G>C	p.Arg459Pro	missense_variant	8/9		NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.1502G>C	p.Arg501Pro	missense_variant	9/10	1	NM_005518.4	ENSP00000358414.3
HMGCS2	ENST00000544913.2	c.1376G>C	p.Arg459Pro	missense_variant	8/9	2		ENSP00000439495.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251332 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-hydroxy-3-methylglutaryl-CoA synthase deficiency Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 18, 2024	Variant summary: HMGCS2 c.1502G>C (p.Arg501Pro) results in a non-conservative amino acid change located in the Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain (IPR013746) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251332 control chromosomes. c.1502G>C has been reported in the literature in compound heterozygous individuals affected with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (e.g. Rojnueangnit_2020, Williams_2024). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absent 3-hydroxy-3-methylglutaryl CoA synthase activity in vitro (Bagheri-Fam_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31910233, 33045405, 38469099). ClinVar contains an entry for this variant (Variation ID: 452101). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with HMGCS2 related disorder (PMID: 33045405). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 31910233, 33045405). A different missense change at the same codon (p.Arg501Gln) has been reported to be associated with HMGCS2 related disorder (PMID: 30477625). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	research	Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University	Mar 15, 2020	The patient is affected with Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) and harbors the compound heterozygous HMGCS2 mutations, c.1480C>T, p.Arg494* (SCV 001169710 assigned) inherited from his father and c.1502G>C, p.Arg501Pro from his mother. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 02, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 501 of the HMGCS2 protein (p.Arg501Pro). This variant is present in population databases (rs372079931, gnomAD 0.01%). This missense change has been observed in individual(s) with HMG-CoA synthase deficiency (PMID: 33045405; Invitae). 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: 452101). 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 HMGCS2 protein function. Experimental studies have shown that this missense change affects HMGCS2 function (PMID: 31910233). This variant disrupts the p.Arg501 amino acid residue in HMGCS2. Other variant(s) that disrupt this residue have been observed in individuals with HMGCS2-related conditions (PMID: 30477625), which suggests that this may be a clinically significant amino acid residue. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2024

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 31910233); 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; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 34963118, 33045405, 38469099, 31910233, 30477625, 35308163) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.81		Loss of MoRF binding (P = 7e-04);.;
MVP		0.98
MPC		0.62
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs372079931; hg19: chr1-120293450;