NM_001352514.2(HLCS):c.1942del (p.Arg648fs) AND Holocarboxylase synthetase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 18, 2024
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:: RCV002310362.3

Allele description [Variation Report for NM_001352514.2(HLCS):c.1942del (p.Arg648fs)]

NM_001352514.2(HLCS):c.1942del (p.Arg648fs)

Gene:

HLCS:holocarboxylase synthetase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

21q22.13

Genomic location:

Preferred name:

NM_001352514.2(HLCS):c.1942del (p.Arg648fs)

HGVS:

NC_000021.9:g.36767238del
NG_016193.2:g.228159del
NM_000411.7:c.1501del
NM_000411.8:c.1501del
NM_001242784.3:c.1501del
NM_001242785.2:c.1501del
NM_001352514.2:c.1942delMANE SELECT
NM_001352515.2:c.1501del
NM_001352516.2:c.1501del
NM_001352517.1:c.1501del
NM_001352518.2:c.1501del
NP_000402.3:p.Arg501fs
NP_001229713.1:p.Arg501fs
NP_001229714.1:p.Arg501fs
NP_001339443.1:p.Arg648fs
NP_001339444.1:p.Arg501fs
NP_001339445.1:p.Arg501fs
NP_001339446.1:p.Arg501fs
NP_001339447.1:p.Arg501fs
NC_000021.8:g.38139539del
NR_148020.2:n.1801del
NR_148021.1:n.1958del

Protein change:

R501fs

Links:

dbSNP: rs2090070597

Molecular consequence:

NM_000411.8:c.1501del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001242784.3:c.1501del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001242785.2:c.1501del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352514.2:c.1942del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352515.2:c.1501del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352516.2:c.1501del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352517.1:c.1501del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352518.2:c.1501del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_148020.2:n.1801del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148021.1:n.1958del - 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
SCV002602346	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Dec 30, 2021)	unknown	clinical testing	Citation Link,
SCV007530314	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Likely pathogenic (Jun 18, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002602346

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely pathogenic
(Dec 30, 2021)

unknown

clinical testing

Citation Link,

SCV007530314

Natera, Inc.

criteria provided, single submitter

(Natera Variant Classification Schema (03/2026))

Likely pathogenic
(Jun 18, 2024)

germline

clinical testing

Citation Link

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

Details of each submission

From Myriad Genetics, Inc., SCV002602346.2

#	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.1501delC(R501Gfs*14) 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 Natera, Inc., SCV007530314.1

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

Description

The c.1501del variant in HLCS is a frameshift variant predicted to shift the reading frame beginning at codon 501 and leads to a stop codon 14 codons downstream. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely 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

Last Updated: Apr 12, 2026

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