chr1-23820545-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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. 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

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.29
Variant links:
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]

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ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
HMGCLNM_000191.3 linkc.109G>T p.Glu37* stop_gained Exon 2 of 9 ENST00000374490.8 NP_000182.2 P35914-1
HMGCLNM_001166059.2 linkc.109G>T p.Glu37* stop_gained Exon 2 of 7 NP_001159531.1 P35914-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HMGCLENST00000374490.8 linkc.109G>T p.Glu37* stop_gained Exon 2 of 9 1 NM_000191.3 ENSP00000363614.3 P35914-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:9
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. -

Mar 28, 2017
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 10, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

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 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 30, 2024
Baylor 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
Dec 04, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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) -

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 v4.3

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763494292; hg19: chr1-24147035; API