VCV000011954.14 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 11954 Accession: VCV000011954.14

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 1p36.11 1: 23817521-23817522 (GRCh38) [ NCBI UCSC ] 1: 24144011-24144012 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 13, 2015	Jun 17, 2024	Feb 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000191.3:c.206_207del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000182.2:p.Ser69fs	frameshift
NM_000191.3:c.206_207delCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000191.2:c.206_207del
NM_001166059.2:c.206_207del	NP_001159531.1:p.Ser69fs	frameshift
NC_000001.11:g.23817521AG[2]
NC_000001.10:g.24144011AG[2]
NG_013061.1:g.12934CT[2]

... more HGVS ... less HGVS

Protein change

S69fs

Other names

Canonical SPDI

NC_000001.11:23817520:AGAGAG:AGAG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA256129 OMIM: 613898.0001 dbSNP: rs752137615 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HMGCL		-	-	GRCh38 GRCh37	510	528

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Deficiency of hydroxymethylglutaryl-CoA lyase	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Feb 29, 2024	RCV000012732.14
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 22, 2022	RCV000185970.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 09, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001983424.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Publications: PubMed (1) PubMed: 8440722 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238928.8 First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8440722, 19177531, 35646072) (less)
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004172714.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (Jan 14, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001381603.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 9817922‚ 17692550‚ 23465862‚ 8440722 Comment: This sequence change creates a premature translational stop signal (p.Ser69Cysfs11) in the HMGCL gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ser69Cysfs11) 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. (less)
Likely pathogenic (Mar 29, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790562.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 8440722
Pathogenic (Feb 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004199896.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Feb 25, 1993)	no assertion criteria provided Method: literature only	HMG-CoA LYASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032967.3 First in ClinVar: Apr 04, 2013 Last updated: May 13, 2015	Publications: PubMed (1) PubMed: 8440722 Mitchell, G. A., Robert, M.-F., (more...) 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. Comment on evidence: 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 … (more) 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. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	HMG-CoA lyase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001459894.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

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.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8440722, 19177531, 35646072)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of aberrant splicing and nonsense-mediated decay of the stop codon mutations c.109G>T and c.504_505delCT in 7 patients with HMG-CoA lyase deficiency.	Puisac B	Molecular genetics and metabolism	2013	PMID: 23465862
Molecular genetics of HMG-CoA lyase deficiency.	Pié J	Molecular genetics and metabolism	2007	PMID: 17692550
3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice.	Wang SP	Human molecular genetics	1998	PMID: 9817922
3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency.	Mitchell GA	The Journal of biological chemistry	1993	PMID: 8440722
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.	-	-	-	-

Text-mined citations for rs752137615 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs752137615 ...