NM_000191.3(HMGCL):c.914_915del (p.Phe305fs) AND Deficiency of hydroxymethylglutaryl-CoA lyase

Clinical significance:Pathogenic (Last evaluated: Feb 3, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000032616.8

Allele description [Variation Report for NM_000191.3(HMGCL):c.914_915del (p.Phe305fs)]

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

Gene:
HMGCL:3-hydroxy-3-methylglutaryl-CoA lyase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1p36.11
Genomic location:
Preferred name:
NM_000191.3(HMGCL):c.914_915del (p.Phe305fs)
HGVS:
  • NC_000001.11:g.23802527_23802528del
  • NG_007068.1:g.3278_3279del
  • NG_013061.1:g.27933_27934del
  • NM_000191.3:c.914_915delMANE SELECT
  • NM_001166059.1:c.701_702del
  • NP_000182.2:p.Phe305fs
  • NP_001159531.1:p.Phe234fs
  • NC_000001.10:g.24129017_24129018del
  • NM_000191.2:c.914_915delTT
Protein change:
F234fs
Links:
OMIM: 613898.0006; dbSNP: rs786205431
NCBI 1000 Genomes Browser:
rs786205431
Molecular consequence:
  • NM_000191.3:c.914_915del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001166059.1:c.701_702del - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000056376OMIMno assertion criteria providedPathogenic
(Feb 1, 1998)
germlineliterature only

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

SCV000797207Counsylcriteria provided, single submitter
Pathogenic
(Jan 16, 2018)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000919524Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Sep 24, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001367088Centre for Mendelian Genomics,University Medical Centre Ljubljanacriteria provided, single submitter
Pathogenic
(Feb 3, 2020)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population.

Al-Sayed M, Imtiaz F, Alsmadi OA, Rashed MS, Meyer BF.

BMC Med Genet. 2006 Dec 16;7:86.

PubMed [citation]
PMID:
17173698
PMCID:
PMC1764877

HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.

Mitchell GA, Ozand PT, Robert MF, Ashmarina L, Roberts J, Gibson KM, Wanders RJ, Wang S, Chevalier I, Plöchl E, Miziorko H.

Am J Hum Genet. 1998 Feb;62(2):295-300.

PubMed [citation]
PMID:
9463337
PMCID:
PMC1376904
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000056376.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000797207.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919524.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Centre for Mendelian Genomics,University Medical Centre Ljubljana, SCV001367088.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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