chr21-36756651-C-T

Variant names:

• chr21-36756651-C-T
• rs149399432
• NM_001352514.2:c.2341G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001352514.2(HLCS):​c.2341G>A​(p.Asp781Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D781E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 4.16
• Publications: 6 publications found

Genes affected

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

HLCS Gene-Disease associations (from GenCC):

• holocarboxylase synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-36756651-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2676009.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 21-36756651-C-T is Pathogenic according to our data. Variant chr21-36756651-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 558569.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352514.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.2341G>A	p.Asp781Asn	missense	Exon 10 of 11	NP_001339443.1
	HLCS	NM_000411.8		c.1900G>A	p.Asp634Asn	missense	Exon 11 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.1900G>A	p.Asp634Asn	missense	Exon 11 of 12	NP_001229713.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.2341G>A	p.Asp781Asn	missense	Exon 10 of 11	ENSP00000502087.2
	HLCS	ENST00000336648.8	TSL:1	c.1900G>A	p.Asp634Asn	missense	Exon 11 of 12	ENSP00000338387.3
	HLCS	ENST00000399120.5	TSL:1	c.1900G>A	p.Asp634Asn	missense	Exon 11 of 12	ENSP00000382071.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152046 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251496 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41506

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0265 Hom.: 2349

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Holocarboxylase synthetase deficiency Pathogenic:2 Uncertain:2

Jun 20, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with HLCS related disorder (ClinVar ID: VCV000558569 /PMID: 12633764).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 12633764, 17274881).A different missense change at the same codon (p.Asp781Tyr) has been reported to be associated with HLCS related disorder (ClinVar ID: VCV002676009 /PMID: 11735028). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 634 of the HLCS protein (p.Asp634Asn). This variant is present in population databases (rs149399432, gnomAD 0.006%). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 12633764, 17274881). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558569). 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 with a positive predictive value of 80%. This variant disrupts the p.Asp634 amino acid residue in HLCS. Other variant(s) that disrupt this residue have been observed in individuals with HLCS-related conditions (PMID: 11735028), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Oct 20, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000411.6(HLCS):c.1900G>A(D634N) is a missense variant classified as a variant of uncertain significance in the context of holocarboxylase synthetase deficiency. D634N has been observed in cases with relevant disease (PMID: 12633764, 17274881, 16134170). Functional assessments of this variant are not available in the literature. D634N has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000411.6(HLCS):c.1900G>A(D634N) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Oct 13, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:1

Mar 10, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16134170, 25087612, 12633764, 17274881)

not specified Uncertain:1

Jun 12, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HLCS c.1900G>A (p.Asp634Asn) results in a conservative amino acid change located in the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domain of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 1.6e-05 in 251496 control chromosomes. c.1900G>A has been observed in individual(s) affected with Holocarboxylase Synthetase Deficiency. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17274881, 12633764). ClinVar contains an entry for this variant (Variation ID: 558569). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	0.0068	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.017	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.59
MVP		0.98
MPC		0.57
ClinPred		0.71	D
GERP RS		4.7
Varity_R		0.14
gMVP		0.66
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149399432; hg19: chr21-38128952; COSMIC: COSV60794779;