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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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001373275Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jan 27, 2022)
germlineclinical testing

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

SCV002060025Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))
Uncertain significance
(Nov 8, 2021)
unknownclinical testing

Citation Link,

SCV004172434Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 11, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

From Myriad Genetics, Inc., SCV002060025.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

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

From Genome-Nilou Lab, SCV004172434.1

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

Last Updated: Sep 29, 2024