NM_000191.3(HMGCL):c.614C>G (p.Thr205Ser) AND Deficiency of hydroxymethylglutaryl-CoA lyase

Germline classification:: Uncertain significance (3 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:: RCV001202170.11

Allele description [Variation Report for NM_000191.3(HMGCL):c.614C>G (p.Thr205Ser)]

NM_000191.3(HMGCL):c.614C>G (p.Thr205Ser)

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.614C>G (p.Thr205Ser)

HGVS:

NC_000001.11:g.23808271G>C
NG_013061.1:g.22189C>G
NM_000191.3:c.614C>GMANE SELECT
NM_001166059.2:c.401C>G
NP_000182.2:p.Thr205Ser
NP_001159531.1:p.Thr134Ser
NC_000001.10:g.24134761G>C
NM_000191.2:c.614C>G

Protein change:

T134S

Links:

dbSNP: rs1445870588

NCBI 1000 Genomes Browser:

rs1445870588

Molecular consequence:

NM_000191.3:c.614C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001166059.2:c.401C>G - 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
SCV001373275	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28747690, 28492532
SCV002060025	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 8, 2021)	unknown	clinical testing	Citation Link,
SCV004172434	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001373275

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2022)

germline

clinical testing

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

SCV002060025

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))

Uncertain significance
(Nov 8, 2021)

unknown

clinical testing

Citation Link,

SCV004172434

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]

Help

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	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

Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death.

Oshima Y, Yamamoto T, Ishikawa T, Mishima H, Matsusue A, Umehara T, Murase T, Abe Y, Kubo SI, Yoshiura KI, Makita N, Ikematsu K.

J Hum Genet. 2017 Nov;62(11):989-995. doi: 10.1038/jhg.2017.79. Epub 2017 Jul 27.

PubMed [citation]

PMID:: 28747690

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001373275.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 205 of the HMGCL protein (p.Thr205Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sudden unexpected death (PMID: 28747690). ClinVar contains an entry for this variant (Variation ID: 933868). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 Myriad Genetics, Inc., SCV002060025.2

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

Description

NM_000191.2(HMGCL):c.614C>G(T205S) is a missense variant classified as a variant of uncertain significance in the context of HMG-CoA lyase deficiency. T205S has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. T205S has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000191.2(HMGCL):c.614C>G(T205S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	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, SCV004172434.1

#	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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