VCV000001145.18 - ClinVar

NM_014362.4(HIBCH):c.365A>G (p.Tyr122Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014362.4(HIBCH):c.365A>G (p.Tyr122Cys)

Variation ID: 1145 Accession: VCV000001145.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 190290425 (GRCh38) [ NCBI UCSC ] 2: 191155151 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 28, 2015	Jun 9, 2024	Dec 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_014362.4:c.365A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055177.2:p.Tyr122Cys	missense
NM_198047.3:c.365A>G	NP_932164.1:p.Tyr122Cys	missense
NC_000002.12:g.190290425T>C
NC_000002.11:g.191155151T>C
NG_017062.1:g.34621A>G
	Q6NVY1:p.Tyr122Cys

... more HGVS ... less HGVS

Protein change

Y122C

Other names

Canonical SPDI

NC_000002.12:190290424:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00006

Links

ClinGen: CA114798 UniProtKB: Q6NVY1#VAR_031870 OMIM: 610690.0002 dbSNP: rs121918329 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HIBCH		-	-	GRCh38 GRCh37	216	246

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Beta-hydroxyisobutyryl-CoA deacylase deficiency	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Dec 19, 2023	RCV000001204.14
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 25, 2022	RCV000224374.7
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Feb 8, 2019	RCV000623332.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 17, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281100.2 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Likely pathogenic (Oct 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Beta-hydroxyisobutyryl-CoA deacylase deficiency Affected status: unknown Allele origin: germline	SIB Swiss Institute of Bioinformatics Accession: SCV000883163.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: This variant is interpreted as Likely Pathogenic, for 3-hydroxyisobutryl-CoA hydrolase deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or … (more) This variant is interpreted as Likely Pathogenic, for 3-hydroxyisobutryl-CoA hydrolase deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate. PM3-Supporting => PM3 downgraded in strength to Supporting. (less)
Pathogenic (Sep 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491308.5 First in ClinVar: Jun 08, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect (reduction of enzyme activity) (Loupatty et al., 2007); In silico analysis supports that this missense variant has a … (more) Published functional studies demonstrate a damaging effect (reduction of enzyme activity) (Loupatty et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27896122, 26717663, 17160907, 31589614, 32677093) (less)
Likely pathogenic (Jun 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Beta-hydroxyisobutyryl-CoA deacylase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002305007.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 27896122‚ 17160907‚ 32677093 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects HIBCH function (PMID: 27896122). 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 HIBCH protein function. ClinVar contains an entry for this variant (Variation ID: 1145). This missense change has been observed in individual(s) with 3-hydroxyisobutryl-CoA hydrolase deficiency (PMID: 17160907, 32677093; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121918329, gnomAD 0.04%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the HIBCH protein (p.Tyr122Cys). (less)
Likely pathogenic (Feb 08, 2019)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741820.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (2) PubMed: 17160907‚ 27896122 Observation 1: Number of individuals with the variant: 1 Clinical Features: Muscular hypotonia (present) , Neurodevelopmental delay (present) , Abnormality of eye movement (present) , Hyperactive deep tendon reflexes (present) , Aspiration (present) , Gait imbalance … (more) Muscular hypotonia (present) , Neurodevelopmental delay (present) , Abnormality of eye movement (present) , Hyperactive deep tendon reflexes (present) , Aspiration (present) , Gait imbalance (present) , Growth delay (present) , Abnormality of brain morphology (present) , Short nose (present) , Downturned corners of mouth (present) , Kyphosis (present) , Cafe-au-lait spot (present) , Brisk reflexes (present) , Titubation (present) , Dysmetria (present) (less) Sex: male Ethnicity/Population group: Hispanic Observation 2: Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Developmental regression (present) , Gait ataxia (present) , Tremor (present) , Encephalopathy (present) , Seizures (present) , Muscle weakness (present) … (more) Global developmental delay (present) , Developmental regression (present) , Gait ataxia (present) , Tremor (present) , Encephalopathy (present) , Seizures (present) , Muscle weakness (present) , Muscular hypotonia (present) , Abnormality of the globus pallidus (present) , Heart murmur (present) , Nystagmus (present) , Oculomotor apraxia (present) (less) Sex: female Ethnicity/Population group: Hispanic
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-hydroxyisobutyryl-CoA deacylase deficiency Affected status: yes Allele origin: unknown	3billion Accession: SCV003841978.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (2) PubMed: 17160907‚ 27896122 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Functional studies provide moderate evidence of the … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17160907, 27896122). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001145). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Polyneuropathy (present) , Developmental regression (present) , Motor delay (present)
Pathogenic (Dec 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-hydroxyisobutyryl-CoA deacylase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001525528.3 First in ClinVar: Mar 22, 2021 Last updated: Jun 09, 2024
Pathogenic (Jan 01, 2007)	no assertion criteria provided Method: literature only	3-@HYDROXYISOBUTYRYL-CoA HYDROLASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021354.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 28, 2015	Publications: PubMed (1) PubMed: 17160907 Comment on evidence: In a patient with 3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD; 250620), Loupatty et al. (2007) found compound heterozygosity for 2 mutations in the HIBCH gene. The patient … (more) In a patient with 3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD; 250620), Loupatty et al. (2007) found compound heterozygosity for 2 mutations in the HIBCH gene. The patient presented with progressive infantile neurodegeneration and was born of nonconsanguineous parents. The patient had no structural abnormalities of the brain or heart and no dysmorphic facial features, and was alive at time of report. The 2 mutations were a 365A-G transition resulting in a tyr122-to-cys substitution (Y122C) carried on the maternal allele, and a splice acceptor site mutation, IVS2-3C-G (610690.0003), carried on the paternal allele. The missense mutation predicted the substitution of the bulky amino acid residue tyrosine, which is conserved among different species. The splice site transversion disrupted the consensus sequence for a splice acceptor site, given that a pyrimidine (cytosine or thymine) is preferred over guanine at this position in the consensus sequence. The significance of this mutation on splicing was investigated by analysis of HIBCH cDNA. Sequence analysis revealed a heterozygous 2-bp insertion resulting from retention of the 3-prime end of intron 2, causing a frameshift (Arg27fsTer50). The intronic DNA sequence adjacent to the IVS2-3C-G mutation showed strong homology to the consensus sequence of a splice acceptor site, with identity at 9 of 10 intronic bases. Loupatty et al. (2007) found that heterozygosity for the 2 mutations resulted in complete absence of HIBCH activity in the patient, indicative of a pathogenetic effect in both mutations. (less)
Uncertain significance (Apr 01, 2020)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Beta-hydroxyisobutyryl-CoA deacylase deficiency Affected status: unknown Allele origin: paternal, maternal	Elsea Laboratory, Baylor College of Medicine Accession: SCV001424227.1 First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020	Observation 1: Sex: male Testing laboratory: Org: 1006 Observation 2: Sex: male Testing laboratory: Org: 1006
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This variant is interpreted as Likely Pathogenic, for 3-hydroxyisobutryl-CoA hydrolase deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate. PM3-Supporting => PM3 downgraded in strength to Supporting.

Comment:

Published functional studies demonstrate a damaging effect (reduction of enzyme activity) (Loupatty et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27896122, 26717663, 17160907, 31589614, 32677093)

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects HIBCH function (PMID: 27896122). 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 HIBCH protein function. ClinVar contains an entry for this variant (Variation ID: 1145). This missense change has been observed in individual(s) with 3-hydroxyisobutryl-CoA hydrolase deficiency (PMID: 17160907, 32677093; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121918329, gnomAD 0.04%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the HIBCH protein (p.Tyr122Cys).

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17160907, 27896122). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001145). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.	Marti-Sanchez L	Journal of inherited metabolic disease	2021	PMID: 32677093
Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis.	Yamada K	Molecular genetics and metabolism reports	2014	PMID: 27896122
Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration.	Loupatty FJ	American journal of human genetics	2007	PMID: 17160907

Text-mined citations for rs121918329 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_014362.4(HIBCH):c.365A>G (p.Tyr122Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918329 ...