NM_000191.3(HMGCL):c.206_207del (p.Ser69fs) AND Deficiency of hydroxymethylglutaryl-CoA lyase

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Feb 29, 2024
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:: RCV000012732.14

Allele description [Variation Report for NM_000191.3(HMGCL):c.206_207del (p.Ser69fs)]

NM_000191.3(HMGCL):c.206_207del (p.Ser69fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

1p36.11

Genomic location:

Preferred name:

NM_000191.3(HMGCL):c.206_207del (p.Ser69fs)

HGVS:

NC_000001.11:g.23817521AG[2]
NG_013061.1:g.12934CT[2]
NM_000191.3:c.206_207delMANE SELECT
NM_001166059.2:c.206_207del
NP_000182.2:p.Ser69fs
NP_001159531.1:p.Ser69fs
NC_000001.10:g.24144011AG[2]
NC_000001.10:g.24144011_24144012del
NM_000191.2:c.206_207del
NM_000191.2:c.206_207delCT
NM_000191.3:c.206_207delCTMANE SELECT
p.S69CfsX11

Protein change:

S69fs

Links:

OMIM: 613898.0001; dbSNP: rs752137615

NCBI 1000 Genomes Browser:

rs752137615

Molecular consequence:

NM_000191.3:c.206_207del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001166059.2:c.206_207del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Deficiency of hydroxymethylglutaryl-CoA lyase (HMGCLD)
Synonyms:: HMG CoA lyase deficiency; Defect in leucine metabolism; 3-hydroxy-3-methylglutaric aciduria; 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
SCV000032967	OMIM	no assertion criteria provided	Pathogenic (Feb 25, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID] Mitchell, G. A., Robert, M.-F., Fontaine, G., Wang, S., Lambert, M., Cole, D., Lee, C., Gibson, M., Miziorko, H. HMG CoA lyase (HL) deficiency: detection of a causal mutation in an affected French-Canadian sibship. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A173, 1992.,
SCV000790562	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 29, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001381603	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9817922, 17692550, 23465862, 8440722, 28492532
SCV001459894	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001983424	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004172714	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]
SCV004199896	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 29, 2024)	unknown	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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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 OMIM, SCV000032967.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an Acadian French Canadian family in which 2 sibs had episodes of hypoglycemia and coma, urinary organic acids, and enzymologic findings typical of HMG-CoA lyase deficiency (HMGCLD; 246450), Mitchell et al. (1992, 1993) used single-strand conformation polymorphism (SSCP) analysis and detected a 2-bp deletion within the sequence CTCTCT, nucleotides 202-207 of the HMGCL cDNA. The mutation created a frameshift within the serine-69 codon, S69fs(-2), that resulted in a truncated 78-residue HMG-CoA lyase peptide in which 8 of the 10 residues differed from the normal and were predicted to be nonfunctional. Both parents were heterozygous for the mutation and the affected sibs were homozygous. None of 12 other lyase-deficient probands, of 9 different ethnic origins, showed this mutation. The mutation was also absent in a Quebec French Canadian patient who was a genetic compound for a val70-to-leu mutation (V70L; 613898.0002) and a second, as yet unidentified allele. Thus, at least 3 mutant alleles had been identified in the French Canadian population.

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

From Counsyl, SCV000790562.1

#	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, SCV001381603.4

#	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.Ser69Cysfs*11) 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 present in population databases (rs752137615, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 8440722). It has also been observed to segregate with disease in related individuals. This variant is also known as S69fs(-2). ClinVar contains an entry for this variant (Variation ID: 11954). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Natera, Inc., SCV001459894.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983424.1

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

Description

Variant summary: HMGCL c.206_207delCT (p.Ser69CysfsX11) 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 2.8e-05 in 251468 control chromosomes. c.206_207delCT has been reported in the literature in individuals affected with HMG-CoA Lyase Deficiency (e.g. Mitchell_1993). 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 <10% of normal activity (Mitchell_1993). Four 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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, SCV004172714.1

#	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

From Baylor Genetics, SCV004199896.2

#	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

Last Updated: Sep 29, 2024

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