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

gnomAD frequency: 0.00001  dbSNP: rs121918329

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224374	SCV000281100	pathogenic	not provided	2015-09-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000224374	SCV000491308	pathogenic	not provided	2022-09-25	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000623332	SCV000741820	likely pathogenic	Inborn genetic diseases	2019-02-08	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000001204	SCV000883163	likely pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2018-10-15	criteria provided, single submitter	curation	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.
Elsea Laboratory, Baylor College of Medicine	RCV000001204	SCV001424227	uncertain significance	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2020-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000001204	SCV001525528	pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2022-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV000001204	SCV002305007	likely pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2023-06-04	criteria provided, single submitter	clinical testing	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).
3billion	RCV000001204	SCV003841978	pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2023-02-23	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000001204	SCV000021354	pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2007-01-01	no assertion criteria provided	literature only