NM_000191.3(HMGCL):c.286C>T (p.Gln96Ter) AND Deficiency of hydroxymethylglutaryl-CoA lyase

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000673631.5

Allele description [Variation Report for NM_000191.3(HMGCL):c.286C>T (p.Gln96Ter)]

NM_000191.3(HMGCL):c.286C>T (p.Gln96Ter)

Gene:

HMGCL:3-hydroxy-3-methylglutaryl-CoA lyase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.11

Genomic location:

Preferred name:

NM_000191.3(HMGCL):c.286C>T (p.Gln96Ter)

HGVS:

NC_000001.11:g.23816737G>A
NG_013061.1:g.13723C>T
NM_000191.3:c.286C>TMANE SELECT
NM_001166059.2:c.286C>T
NP_000182.2:p.Gln96Ter
NP_001159531.1:p.Gln96Ter
NC_000001.10:g.24143227G>A
NM_000191.2:c.286C>T

Protein change:

Q96*

Links:

dbSNP: rs890995574

NCBI 1000 Genomes Browser:

rs890995574

Molecular consequence:

NM_000191.3:c.286C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001166059.2:c.286C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Deficiency of hydroxymethylglutaryl-CoA lyase (HMGCLD)
Synonyms:: Defect in leucine metabolism; 3-hydroxy-3-methylglutaric aciduria; HMG-CoA LYASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009520; MedGen: C0268601; Orphanet: 20; OMIM: 246450

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000798857	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 27, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003523183	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9817922, 17692550, 23465862, 11461194, 28492532
SCV004172659	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000798857

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Mar 27, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV003523183

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 2, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004172659

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 11, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice.

Wang SP, Marth JD, Oligny LL, Vachon M, Robert MF, Ashmarina L, Mitchell GA.

Hum Mol Genet. 1998 Dec;7(13):2057-62.

PubMed [citation]

PMID:: 9817922

Molecular genetics of HMG-CoA lyase deficiency.

Pié J, López-Viñas E, Puisac B, Menao S, Pié A, Casale C, Ramos FJ, Hegardt FG, Gómez-Puertas P, Casals N.

Mol Genet Metab. 2007 Nov;92(3):198-209. Epub 2007 Aug 9. Review.

PubMed [citation]

PMID:: 17692550

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000798857.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003523183.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Gln96*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 11461194). ClinVar contains an entry for this variant (Variation ID: 557482). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004172659.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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