NM_000191.3(HMGCL):c.208G>C (p.Val70Leu) AND Deficiency of hydroxymethylglutaryl-CoA lyase

Germline classification:: Uncertain significance (5 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:: RCV000012733.9

Allele description [Variation Report for NM_000191.3(HMGCL):c.208G>C (p.Val70Leu)]

NM_000191.3(HMGCL):c.208G>C (p.Val70Leu)

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.208G>C (p.Val70Leu)

HGVS:

NC_000001.11:g.23817520C>G
NG_013061.1:g.12940G>C
NM_000191.3:c.208G>CMANE SELECT
NM_001166059.2:c.208G>C
NP_000182.2:p.Val70Leu
NP_001159531.1:p.Val70Leu
NC_000001.10:g.24144010C>G
NM_000191.2:c.208G>C
P35914:p.Val70Leu

Protein change:

V70L; VAL70LEU

Links:

UniProtKB: P35914#VAR_003748; OMIM: 613898.0002; dbSNP: rs121964996

NCBI 1000 Genomes Browser:

rs121964996

Molecular consequence:

NM_000191.3:c.208G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001166059.2:c.208G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000032968	OMIM	no assertion criteria provided	Pathogenic (May 8, 2015)	germline	literature only	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.,
SCV000800541	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 23, 2017)	unknown	clinical testing	Citation Link,
SCV002168999	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002799582	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004172703	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000032968.2

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

Description

In a French Canadian patient in Quebec with HMG-CoA lyase deficiency (HMGCLD; 246450), Mitchell et al. (1992) found compound heterozygosity for a G-to-C transversion at nucleotide 208 of the HMGCL gene, resulting in a missense mutation in which the normal val70 codon was replaced by leucine (V70L); the other allele was as yet unidentified.

#	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, SCV000800541.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002168999.2

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

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 70 of the HMGCL protein (p.Val70Leu). This variant is present in population databases (rs121964996, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HMGCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 11955). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002799582.1

#	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 Genome-Nilou Lab, SCV004172703.1

#	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: Sep 29, 2024

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