rs763494292

chr1-23820545-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000191.3(HMGCL):c.109G>T(p.Glu37Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,004 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: HMGCL NM_000191.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.29

Genes affected

HMGCL (HGNC:5005): (3-hydroxy-3-methylglutaryl-CoA lyase) The protein encoded by this gene belongs to the HMG-CoA lyase family. It is a mitochondrial enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Mutations in this gene are associated with HMG-CoA lyase 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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-23820545-C-A is Pathogenic according to our data. Variant chr1-23820545-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 195033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-23820545-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCL	NM_000191.3	c.109G>T	p.Glu37Ter	stop_gained	2/9	ENST00000374490.8
HMGCL	NM_001166059.2	c.109G>T	p.Glu37Ter	stop_gained	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCL	ENST00000374490.8	c.109G>T	p.Glu37Ter	stop_gained	2/9	1	NM_000191.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251488 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 06, 2023	ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 09, 2018	The HMGCL c.109G>T (p.Glu37Ter) variant is a stop-gained variant that is predicted to cause premature truncation of the protein. In a selection of the available literature, the p.Glu37Ter variant was found in at least 11 unrelated individuals affected with 3-hydroxy-3-methylglutaryl-Coenzyme A lyase deficiency, including in eight individuals in a homozygous state, in two in a compound heterozygous state and in one in a heterozygous state in whom the second variant was not found (Pié et al. 1997; Cardoso et al. 2004). The variant was shown to be absent from one control individual but is reported at a frequency of 0.000208 in the Latino population of the Genome Aggregation Database. In patiet fibroblasts, 3-hydroxy-3-methylglutaryl-Coenzyme A lyase activity was shown to be less than 3% of activity compared to the levels seen in healthy subjects (Pié et al. 1997; Cardoso et al. 2004). RT-PCR analysis in patient fibroblasts showed that the variant resulted in skipping of exon 2 (Pié et al. 1997). Based on the collective evidence and the potential impact of stop-gained variants, the p.Glu37Ter variant is classified as pathogenic for 3-hydroxy-3-methylglutaryl-Coenzyme A lyase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2018	Variant summary: HMGCL c.109G>T (p.Glu37X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.9e-05 in 246260 control chromosomes, which does not exceed the maximal expected allele frequency for a pathogenic variant in HMGCL. c.109G>T has been reported in the literature in multiple individuals affected with HMG-CoA Lyase Deficiency as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. In a report by Casale_1998, four patients homozygous for the variant had HMG-CoA lyase activity levels less than 10% of controls, indicating a severe reduction in enzyme activity caused by the variant. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	This sequence change creates a premature translational stop signal (p.Glu37*) in the HMGCL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 289 amino acid(s) of the HMGCL protein. This variant is present in population databases (rs763494292, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 15308132, 19177531, 23465862, 28583327). 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: 195033). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19177531, 15752612, 18080783, 25525159, 9439591, 15308132, 17692550, 28583327, 28257639, 31589614, 28396157, 9163320, 23465862) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2014	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.109G>T (p.E37*) alteration, located in exon 2 (coding exon 2) of the HMGCL gene, consists of a G to T substitution at nucleotide position 109. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 37. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been report in several homozygous and compound heterozygous individuals with HMG-CoA lyase deficiency (Pié, 1997; Cardoso, 2004; Menao, 2009; Muñoz-Bonet, 2017). Analysis of patient fibroblasts demonstrated that this mutation resulted in exon 2 skipping (Puisac, 2013). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.48
ClinPred		0.89	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs763494292; hg19: chr1-24147035;