chr1-23820545-C-A

Variant names:

• chr1-23820545-C-A
• rs763494292
• NM_000191.3:c.109G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000191.3(HMGCL):​c.109G>T​(p.Glu37*) 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. 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
• Publications: 11 publications found

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]

HMGCL Gene-Disease associations (from GenCC):

• 3-hydroxy-3-methylglutaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-23820545-C-A is Pathogenic according to our data. Variant chr1-23820545-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 195033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000191.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	NM_000191.3	MANE Select	c.109G>T	p.Glu37*	stop_gained	Exon 2 of 9	NP_000182.2
	HMGCL	NM_001166059.2		c.109G>T	p.Glu37*	stop_gained	Exon 2 of 7	NP_001159531.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	ENST00000374490.8	TSL:1 MANE Select	c.109G>T	p.Glu37*	stop_gained	Exon 2 of 9	ENSP00000363614.3
	HMGCL	ENST00000509389.5	TSL:1	n.121G>T		non_coding_transcript_exon	Exon 2 of 6
	HMGCL	ENST00000436439.6	TSL:2	c.109G>T	p.Glu37*	stop_gained	Exon 2 of 7	ENSP00000389281.2

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

GnomAD2 exomes AF: 0.0000477 AC: 12 AN: 251488 AF XY: 0.0000515

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111946

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

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

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.000655 AC: 10 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000275 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

Jan 06, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong, PP4

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jun 11, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 09, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Jun 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Dec 04, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Jun 18, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
PhyloP100		7.3
Vest4		0.48
ClinPred		0.89	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs763494292; hg19: chr1-24147035;