rs767533946
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001352514.2(HLCS):c.1974_1975insT(p.Val659CysfsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
HLCS
NM_001352514.2 frameshift
NM_001352514.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.40
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 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 21-36765158-C-CA is Pathogenic according to our data. Variant chr21-36765158-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 370850.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HLCS | NM_001352514.2 | c.1974_1975insT | p.Val659CysfsTer65 | frameshift_variant | 8/11 | ENST00000674895.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HLCS | ENST00000674895.3 | c.1974_1975insT | p.Val659CysfsTer65 | frameshift_variant | 8/11 | NM_001352514.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152230Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
13
AN:
152230
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251434Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135902
GnomAD3 exomes
AF:
AC:
12
AN:
251434
Hom.:
AF XY:
AC XY:
8
AN XY:
135902
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000231 AC: 337AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.000237 AC XY: 172AN XY: 727244
GnomAD4 exome
AF:
AC:
337
AN:
1461882
Hom.:
Cov.:
32
AF XY:
AC XY:
172
AN XY:
727244
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74372
GnomAD4 genome
?
AF:
AC:
13
AN:
152230
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
74372
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Holocarboxylase synthetase deficiency Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 13, 2018 | The HLCS c.1533dupT (p.Val512CysfsTer65) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Val512CysfsTer65 variant has been reported in two studies, in which it is found in two individuals with holocarboxylase synthetase deficiency, including in a compound heterozygous state in one individual and in a heterozygous state in a second individual who also carries two additional missense variants of unknown phase (DaRe et al. 2013; Reid et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000095 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants and evidence from the literature, the p.Val512CysfsTer65 variant is classified as a variant of unknown significance but suspicious for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 22, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Val512Cysfs*65) 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 (rs767533946, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with a mitochondrial disorder (PMID: 24215330). ClinVar contains an entry for this variant (Variation ID: 370850). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Mar 01, 2019 | This frameshifting variant in exon 9 of 12 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a heterozygous change in two patients with suspected metabolic disease (PMID 24215330, 27604308) and classified in the ClinVar database as Likely Pathogenic by a clinical laboratory (Variation ID: 370850). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (15/277210) and thus is presumed to be rare. Based on the available evidence, the c.1533dup, p.Val512CysfsTer65 variant is classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2021 | The c.1533dupT (p.V512Cfs*65) alteration, located in exon 9 (coding exon 6) of the HLCS gene, consists of a duplication of T at position 1533, causing a translational frameshift with a predicted alternate stop codon after 65 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the heterozygous state along with two other HLCS variants in a patient diagnosed with holocarboxylase synthetase deficiency; however, parental testing to determine the phase of these variants was not available (Reid, 2016). Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2023 | Previously reported in a patient with a neurometabolic phenotype who was also found to have a second variant in the HLCS gene (Reid et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24215330, 27604308, 33870574) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at