VCV000031084.18 - ClinVar

NM_000191.3(HMGCL):c.914_915del (p.Phe305fs)

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.

(11)

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.914_915del (p.Phe305fs)

Variation ID: 31084 Accession: VCV000031084.18

Type and length

Deletion, 2 bp

Location

Cytogenetic: 1p36.11 1: 23802526-23802527 (GRCh38) [ NCBI UCSC ] 1: 24129016-24129017 (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	Jan 25, 2025	Jun 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000191.3:c.914_915del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000182.2:p.Phe305fs	frameshift
NM_001166059.1:c.701_702del
NM_001166059.2:c.701_702del	NP_001159531.1:p.Phe234fs	frameshift
NC_000001.11:g.23802527_23802528del
NC_000001.10:g.24129017_24129018del
NG_007068.1:g.3278_3279del
NG_013061.1:g.27933_27934del

... more HGVS ... less HGVS

Protein change

F305fs, F234fs

Other names

Canonical SPDI

NC_000001.11:23802525:AAA:A

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: CA261115 OMIM: 613898.0006 dbSNP: rs786205431 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	514	532

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 (10)	criteria provided, multiple submitters, no conflicts	Jun 18, 2024	RCV000032616.21
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 20, 2015	RCV000724623.4

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 24, 2018)	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: SCV000919524.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (3) PubMed: 9463337‚ 15308132‚ 19177531 Comment: Variant summary: HMGCL c.914_915delTT (p.Phe305TyrfsX10) 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.914_915delTT (p.Phe305TyrfsX10) 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. The variant allele was found at a frequency of 7.2e-06 in 277236 control chromosomes. c.914_915delTT has been reported in the literature in two homozygous individuals affected with HMG-CoA Lyase Deficiency (Mitchell_1998). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Feb 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367088.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
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: SCV004172647.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Likely pathogenic (Jun 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005647111.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (Jan 16, 2018)	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: SCV000797207.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 9463337‚ 17173698
Pathogenic (Feb 20, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232919.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 9463337 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HMGCL Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Nov 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557006.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Comment: PVS1, PM2, PP5, PP4
Pathogenic (Jul 17, 2023)	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: SCV002218242.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 2443756‚ 6085636‚ 9463337‚ 11129331 Comment: This variant is also known as F305 fs(-2) in literature. This sequence change creates a premature translational stop signal (p.Phe305Tyrfs10) in the HMGCL gene. While … (more) This variant is also known as F305 fs(-2) in literature. This sequence change creates a premature translational stop signal (p.Phe305Tyrfs10) in the HMGCL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the HMGCL protein. This variant is present in population databases (rs786205431, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with HMGCL-related conditions (PMID: 2443756, 6085636, 9463337). ClinVar contains an entry for this variant (Variation ID: 31084). This variant disrupts the C-terminus of the HMGCL protein. Other variant(s) that disrupt this region (p.Gln308*) have been observed in individuals with HMGCL-related conditions (PMID: 11129331). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806887.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Mar 04, 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: SCV004199901.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Feb 01, 1998)	no assertion criteria provided Method: literature only	HMG-CoA LYASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056376.3 First in ClinVar: Apr 04, 2013 Last updated: May 13, 2015	Publications: PubMed (1) PubMed: 9463337 Comment on evidence: For discussion of the 2-bp deletion in the HMGCL gene (Phe305fs(-2)) that was found in compound heterozygous state in patients with HMG-CoA lyase deficiency (HMGCLD; … (more) For discussion of the 2-bp deletion in the HMGCL gene (Phe305fs(-2)) that was found in compound heterozygous state in patients with HMG-CoA lyase deficiency (HMGCLD; 246450) by Mitchell et al. (1998), see 613898.0004. (less)
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Comment:

Variant summary: HMGCL c.914_915delTT (p.Phe305TyrfsX10) 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. The variant allele was found at a frequency of 7.2e-06 in 277236 control chromosomes. c.914_915delTT has been reported in the literature in two homozygous individuals affected with HMG-CoA Lyase Deficiency (Mitchell_1998). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variant is also known as F305 fs(-2) in literature. This sequence change creates a premature translational stop signal (p.Phe305Tyrfs*10) in the HMGCL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the HMGCL protein. This variant is present in population databases (rs786205431, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with HMGCL-related conditions (PMID: 2443756, 6085636, 9463337). ClinVar contains an entry for this variant (Variation ID: 31084). This variant disrupts the C-terminus of the HMGCL protein. Other variant(s) that disrupt this region (p.Gln308*) have been observed in individuals with HMGCL-related conditions (PMID: 11129331). This suggests that this may be a clinically significant region of the protein. 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
Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria.	Menao S	Human mutation	2009	PMID: 19177531
Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population.	Al-Sayed M	BMC medical genetics	2006	PMID: 17173698
The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency.	Cardoso ML	Molecular genetics and metabolism	2004	PMID: 15308132
Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency.	Muroi J	Human genetics	2000	PMID: 11129331
HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.	Mitchell GA	American journal of human genetics	1998	PMID: 9463337
3-Hydroxy-3-methylglutaric aciduria: response to carnitine therapy and fat and leucine restriction.	Dasouki M	Journal of inherited metabolic disease	1987	PMID: 2443756
3-Hydroxy-3-methylglutaric aciduria.	Greene CL	Journal of neurogenetics	1984	PMID: 6085636
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HMGCL	-	-	-	-

Text-mined citations for rs786205431 ...

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 Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000191.3(HMGCL):c.914_915del (p.Phe305fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs786205431 ...