NM_001352514.2(HLCS):c.726dup (p.Val243fs) AND Holocarboxylase synthetase deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 24, 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:: RCV002308022.7

Allele description [Variation Report for NM_001352514.2(HLCS):c.726dup (p.Val243fs)]

NM_001352514.2(HLCS):c.726dup (p.Val243fs)

Gene:

HLCS:holocarboxylase synthetase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

21q22.13

Genomic location:

Preferred name:

NM_001352514.2(HLCS):c.726dup (p.Val243fs)

HGVS:

NC_000021.9:g.36937163dup
NG_016193.2:g.58235dup
NM_000411.8:c.285dup
NM_001242784.3:c.285dup
NM_001242785.2:c.285dup
NM_001352514.2:c.726dupMANE SELECT
NM_001352515.2:c.285dup
NM_001352516.2:c.285dup
NM_001352517.1:c.285dup
NM_001352518.2:c.285dup
NP_000402.3:p.Val96fs
NP_001229713.1:p.Val96fs
NP_001229714.1:p.Val96fs
NP_001339443.1:p.Val243fs
NP_001339444.1:p.Val96fs
NP_001339445.1:p.Val96fs
NP_001339446.1:p.Val96fs
NP_001339447.1:p.Val96fs
NC_000021.8:g.38309459_38309460insG
NC_000021.8:g.38309463dup
NR_148020.2:n.585dup
NR_148021.1:n.742dup

Protein change:

V243fs

Links:

dbSNP: rs1388238708

NCBI 1000 Genomes Browser:

rs1388238708

Molecular consequence:

NM_000411.8:c.285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001242784.3:c.285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001242785.2:c.285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352514.2:c.726dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352515.2:c.285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352516.2:c.285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352517.1:c.285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352518.2:c.285dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_148020.2:n.585dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148021.1:n.742dup - 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
SCV002604487	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 25, 2021)	unknown	clinical testing	Citation Link,
SCV003233544	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 3, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16134170, 28492532
SCV004199852	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 24, 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

SCV002604487

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely pathogenic
(Nov 25, 2021)

unknown

clinical testing

Citation Link,

SCV003233544

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 3, 2021)

germline

clinical testing

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

SCV004199852

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 24, 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	unknown	unknown	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

Citations

PubMed

Mutations in the holocarboxylase synthetase gene HLCS.

Suzuki Y, Yang X, Aoki Y, Kure S, Matsubara Y.

Hum Mutat. 2005 Oct;26(4):285-90. Review.

PubMed [citation]

PMID:: 16134170

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 Myriad Genetics, Inc., SCV002604487.2

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

Description

NM_000411.6(HLCS):c.285dupC(V96Rfs*2) is expected to be pathogenic in the context of holocarboxylase synthetase deficiency. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in HLCS, a gene where loss-of-function variants are known to be pathogenic. 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003233544.3

#	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 creates a premature translational stop signal (p.Val96Argfs*2) in the HLCS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HLCS-related conditions. 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

From Baylor Genetics, SCV004199852.1

#	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: May 16, 2025

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