NM_000191.3:c.109G>A

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000191.3(HMGCL):​c.109G>A​(p.Glu37Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,822 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HMGCL NM_000191.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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.

• PS1: Transcript NM_000191.3 (HMGCL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000191.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-23820545-C-T is Pathogenic according to our data. Variant chr1-23820545-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2676029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-23820545-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCL	NM_000191.3	c.109G>A	p.Glu37Lys	missense_variant	Exon 2 of 9	ENST00000374490.8	NP_000182.2
HMGCL	NM_001166059.2	c.109G>A	p.Glu37Lys	missense_variant	Exon 2 of 7		NP_001159531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490.8	c.109G>A	p.Glu37Lys	missense_variant	Exon 2 of 9	1	NM_000191.3	ENSP00000363614.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:2

Dec 30, 2024

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>A (p.Glu37Lys) results in a conservative amino acid change located in the Pyruvate carboxyltransferase domain (IPR000891) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes. c.109G>A has been reported in the literature in two homozygous individuals in one family affected with HMG-CoA Lyase Deficiency (Menao_2009). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in more than 95% reduction in lysase activity in an in vitro biochemical assay (Menao_2009). The following publication have been ascertained in the context of this evaluation (PMID: 19177531). ClinVar contains an entry for this variant (Variation ID: 2676029). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;.
Vest4		0.99
MutPred		0.96		Gain of MoRF binding (P = 0.0016);Gain of MoRF binding (P = 0.0016);
MVP		0.96
MPC		0.24
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-24147035;