rs770225915

chr1-23820533-G-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.121C>T(p.Arg41Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,520 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R41R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HMGCL NM_000191.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.23

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 1-23820533-G-A is Pathogenic according to our data. Variant chr1-23820533-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCL	NM_000191.3	c.121C>T	p.Arg41Ter	stop_gained	2/9	ENST00000374490.8
HMGCL	NM_001166059.2	c.121C>T	p.Arg41Ter	stop_gained	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCL	ENST00000374490.8	c.121C>T	p.Arg41Ter	stop_gained	2/9	1	NM_000191.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461550 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74198

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

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: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 11, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553933). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 9463337). This variant is present in population databases (rs770225915, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg41*) in the HMGCL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HMGCL are known to be pathogenic (PMID: 9817922, 17692550, 23465862). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 26, 2022	Variant summary: HMGCL c.121C>T (p.Arg41X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251480 control chromosomes. c.121C>T has been reported in the literature without a second allele identified in at-least one individual affected with HMG-CoA Lyase Deficiency (example, Mitchell_1998 cited in Menao_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A homozygous nonsense variant was identified, NM_000191.2(HMGCL):c.121C>T in exon 2 of 9 of the HMGCL gene. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 41 of the protein; NP_000182.2(HMGCL):p.(Arg41*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes) and has been previously identified in patients with HMG-CoA lyase deficiency (ClinVar, Mitchell G. et al. (1998)). Other variants predicted to cause NMD have been reported as pathogenic in individuals with HMG-CoA lyase deficiency (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.50
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs770225915; hg19: chr1-24147023; COSMIC: COSV99354092; COSMIC: COSV99354092;