NM_001352514.2(HLCS):c.2567C>T (p.Pro856Leu) AND Holocarboxylase synthetase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 6, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001055711.6

Allele description [Variation Report for NM_001352514.2(HLCS):c.2567C>T (p.Pro856Leu)]

NM_001352514.2(HLCS):c.2567C>T (p.Pro856Leu)

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.2567C>T (p.Pro856Leu)

HGVS:

NC_000021.9:g.36754301G>A
NG_016193.2:g.241094C>T
NM_000411.8:c.2126C>T
NM_001242784.3:c.2126C>T
NM_001242785.2:c.2126C>T
NM_001352514.2:c.2567C>TMANE SELECT
NM_001352515.2:c.2126C>T
NM_001352516.2:c.2126C>T
NM_001352517.1:c.2126C>T
NM_001352518.2:c.2126C>T
NP_000402.3:p.Pro709Leu
NP_001229713.1:p.Pro709Leu
NP_001229714.1:p.Pro709Leu
NP_001339443.1:p.Pro856Leu
NP_001339444.1:p.Pro709Leu
NP_001339445.1:p.Pro709Leu
NP_001339446.1:p.Pro709Leu
NP_001339447.1:p.Pro709Leu
NC_000021.8:g.38126602G>A
NC_000021.8:g.38126602G>A
NM_000411.6:c.2126C>T
NR_148020.2:n.2651C>T
NR_148021.1:n.2808C>T

Protein change:

P709L

Links:

dbSNP: rs1260631800

NCBI 1000 Genomes Browser:

rs1260631800

Molecular consequence:

NM_000411.8:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001242784.3:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001242785.2:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352514.2:c.2567C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352515.2:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352516.2:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352517.1:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352518.2:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148020.2:n.2651C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148021.1:n.2808C>T - 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
SCV001220115	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 10, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27604308, 28492532
SCV002095586	Natera, Inc.	no assertion criteria provided	Uncertain significance (Aug 16, 2020)	germline	clinical testing
SCV004199829	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 6, 2023)	unknown	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

SCV001220115

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 10, 2022)

germline

clinical testing

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

SCV002095586

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Aug 16, 2020)

germline

clinical testing

SCV004199829

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 6, 2023)

unknown

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

Citations

PubMed

Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.

Reid ES, Papandreou A, Drury S, Boustred C, Yue WW, Wedatilake Y, Beesley C, Jacques TS, Anderson G, Abulhoul L, Broomfield A, Cleary M, Grunewald S, Varadkar SM, Lench N, Rahman S, Gissen P, Clayton PT, Mills PB.

Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.

PubMed [citation]

PMID:: 27604308
PMCID:: PMC5091046

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001220115.2

#	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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 709 of the HLCS protein (p.Pro709Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 27604308). ClinVar contains an entry for this variant (Variation ID: 851334). 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 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

From Natera, Inc., SCV002095586.1

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

#	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 Baylor Genetics, SCV004199829.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 4, 2024

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