NM_000191.3(HMGCL):c.144G>T (p.Lys48Asn) AND Deficiency of hydroxymethylglutaryl-CoA lyase

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 15, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003513581.1

Allele description

NM_000191.3(HMGCL):c.144G>T (p.Lys48Asn)

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.144G>T (p.Lys48Asn)

HGVS:

NC_000001.11:g.23820510C>A
NG_013061.1:g.9950G>T
NM_000191.3:c.144G>TMANE SELECT
NM_001166059.2:c.144G>T
NP_000182.2:p.Lys48Asn
NP_001159531.1:p.Lys48Asn
NC_000001.10:g.24147000C>A

Protein change:

K48N

Molecular consequence:

NM_000191.3:c.144G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166059.2:c.144G>T - 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

Recent activity

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chromodomain-helicase-DNA-binding protein 2 isoform 1 [Homo sapiens]
chromodomain-helicase-DNA-binding protein 2 isoform 1 [Homo sapiens]
gi|118421089|ref|NP_001262.3|

Protein
spermine oxidase isoform 1 [Homo sapiens]
spermine oxidase isoform 1 [Homo sapiens]
gi|28559074|ref|NP_787033.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004291762	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19177531, 34573903, 17459752, 17576681, 9536098, 23465862, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004291762

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria.

Menao S, López-Viñas E, Mir C, Puisac B, Gratacós E, Arnedo M, Carrasco P, Moreno S, Ramos M, Gil MC, Pié A, Ribes A, Pérez-Cerda C, Ugarte M, Clayton PT, Korman SH, Serra D, Asins G, Ramos FJ, Gómez-Puertas P, Hegardt FG, Casals N, et al.

Hum Mutat. 2009 Mar;30(3):E520-9. doi: 10.1002/humu.20966.

PubMed [citation]

PMID:: 19177531

An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency.

Boutouchent N, Bourilhon J, Sudrié-Arnaud B, Bonnevalle A, Guyant-Maréchal L, Acquaviva C, Dujardin-Ippolito L, Bekri S, Dabaj I, Tebani A.

Diagnostics (Basel). 2021 Aug 28;11(9). doi:pii: 1561. 10.3390/diagnostics11091561.

PubMed [citation]

PMID:: 34573903
PMCID:: PMC8469356

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV004291762.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 48 of the HMGCL protein (p.Lys48Asn). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with HMG-CoA lyase deficiency (PMID: 17459752, 19177531, 34573903). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HMGCL function (PMID: 17459752). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 23465862). 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

Last Updated: Mar 30, 2024

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