NM_001352514.2(HLCS):c.1132C>G (p.Gln378Glu) AND Holocarboxylase synthetase deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 28, 2021
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:: RCV002775506.2

Allele description [Variation Report for NM_001352514.2(HLCS):c.1132C>G (p.Gln378Glu)]

NM_001352514.2(HLCS):c.1132C>G (p.Gln378Glu)

Gene:

HLCS:holocarboxylase synthetase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.13

Genomic location:

Preferred name:

NM_001352514.2(HLCS):c.1132C>G (p.Gln378Glu)

HGVS:

NC_000021.9:g.36936754G>C
NG_016193.2:g.58641C>G
NM_000411.8:c.691C>G
NM_001242784.3:c.691C>G
NM_001242785.2:c.691C>G
NM_001352514.2:c.1132C>GMANE SELECT
NM_001352515.2:c.691C>G
NM_001352516.2:c.691C>G
NM_001352517.1:c.691C>G
NM_001352518.2:c.691C>G
NP_000402.3:p.Gln231Glu
NP_001229713.1:p.Gln231Glu
NP_001229714.1:p.Gln231Glu
NP_001339443.1:p.Gln378Glu
NP_001339444.1:p.Gln231Glu
NP_001339445.1:p.Gln231Glu
NP_001339446.1:p.Gln231Glu
NP_001339447.1:p.Gln231Glu
NC_000021.8:g.38309054G>C
NR_148020.2:n.991C>G
NR_148021.1:n.1148C>G

Protein change:

Q231E

Molecular consequence:

NM_000411.8:c.691C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001242784.3:c.691C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001242785.2:c.691C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001352514.2:c.1132C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001352515.2:c.691C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001352516.2:c.691C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001352517.1:c.691C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001352518.2:c.691C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148020.2:n.991C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148021.1:n.1148C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Holocarboxylase synthetase deficiency
Synonyms:: MULTIPLE CARBOXYLASE DEFICIENCY, EARLY ONSET
Identifiers:: MONDO: MONDO:0009666; MedGen: C0268581; Orphanet: 79242; OMIM: 253270

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003022543	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 28, 2021)	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

SCV003022543

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 28, 2021)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003022543.1

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

Description

This sequence change replaces glutamine with glutamic acid at codon 231 of the HLCS protein (p.Gln231Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with HLCS-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HLCS protein function. 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

Last Updated: Sep 29, 2024

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