rs146448211

Variant names:

• chr21-36756558-G-A
• rs146448211
• NM_001352514.2:c.2434C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-36756558-G-A
• chr21-36756558-G-C
• chr21-36756558-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001352514.2(HLCS):​c.2434C>T​(p.Arg812*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000292 in 1,610,630 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R812R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: HLCS NM_001352514.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.64
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-36756558-G-A is Pathogenic according to our data. Variant chr21-36756558-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.2434C>T	p.Arg812*	stop_gained	Exon 10 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.2434C>T	p.Arg812*	stop_gained	Exon 10 of 11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151536 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000958

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251488 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1459094 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 725944

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39564

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1109984

Other (OTH) AF: 0.0000498 AC: 3 AN: 60204

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151536 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3 AN XY: 73976

African (AFR) AF: 0.00 AC: 0 AN: 41248

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.0000958 AC: 1 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000441 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Pathogenic:7

Mar 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 30, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg665*) in the HLCS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the HLCS protein. This variant is present in population databases (rs146448211, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 16134170, 27114915, 33123633). ClinVar contains an entry for this variant (Variation ID: 203770). This variant disrupts the C-terminus of the HLCS protein. Other variant(s) that disrupt this region (p.Arg665Aspfs*41) have been observed in individuals with HLCS-related conditions (PMID: 10190325). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -

Jan 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HLCS c.1993C>T (p.Arg665X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. In at least one experimental study, a truncation downstream of this position was found to impair biotinylating activity, suggesting the C-terminal end of the protein is important for its functional activity (e.g. Campeau_2001). The variant allele was found at a frequency of 2.8e-05 in 251488 control chromosomes (gnomAD). c.1993C>T has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (e.g. Suzuki 2005, Donti 2016, Tangeraas_2020). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as likely pathogenic (n=3) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		5.6
Vest4		0.79
GERP RS		3.6
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146448211; hg19: chr21-38128859;