rs772791252

Positions:

chr21-36759829-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001352514.2(HLCS):c.2134C>T(p.Arg712Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000156 in 1,607,176 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R712R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HLCS
NM_001352514.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.28

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-36759829-G-A is Pathogenic according to our data. Variant chr21-36759829-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 426486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2 linkuse as main transcript	c.2134C>T	p.Arg712Ter	stop_gained	9/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3 linkuse as main transcript	c.2134C>T	p.Arg712Ter	stop_gained	9/11		NM_001352514.2	P4	P50747-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251472

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1455024

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724316

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000127

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000502

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holocarboxylase synthetase deficiency

Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 18, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 12, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426486). This premature translational stop signal has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 9870216). This variant is present in population databases (rs772791252, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg565*) 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). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2018	Variant summary: HLCS c.1693C>T (p.Arg565X) 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. The variant allele was found at a frequency of 2e-05 in 246268 control chromosomes. c.1693C>T has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (Sakamoto 1998, Tang 2003, Donti 2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Sakamoto_1998). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 31, 2022	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2017

The R565X nonsense variant in the HLCS gene has been reported previously in association with holocarboxylase synthetase deciency in several unrelated individuals who were heterozygous for R565X and another variant in the HLCS gene (Sakamoto et al., 1998; Tang et al., 2003; Donti et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.79

MutationTaster

Benign

1.0

A;A

Vest4

0.94

GERP RS

3.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over