X-72567970-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_018486.3(HDAC8):c.356C>G(p.Thr119Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_018486.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HDAC8 | ENST00000373573.9 | c.356C>G | p.Thr119Arg | missense_variant | Exon 4 of 11 | 1 | NM_018486.3 | ENSP00000362674.3 | ||
ENSG00000285547 | ENST00000648922.1 | c.356C>G | p.Thr119Arg | missense_variant | Exon 4 of 12 | ENSP00000497072.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 5 Pathogenic:2
A heterozygous missense variation in exon 4 of the HDAC8 gene that results in the amino acid substitution of Arginine for Threonine at codon 119 was detected. The observed variant c.356C>G(p.Thr119Arg) not been reported in the 1000 genomes, ExAC and our internal databases. The in silico prediction of the variant is probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, damaging by LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis suggests the variant to be of de novo origin. In summary, the variant meets our criteria to be classified as pathogenic. -
HDAC c.356C>G results in a non-conservative amino acid change (p.Thr119Arg) located in the Histone deacetylase domain of the encoded protein sequence. The variant is classified as pathogenic, since it is absent in population databases, it is predicted as having a deleterious effect by multiple computational analyses and it is a de novo variant. Moreover, a c.356C>T transition has been described (Yuan et al., 2015) and two clinical diagnostic laboratories submitted pathogenic classifications for this variant to ClinVar. To date, 48 unique deleterious variants have been reported in HDAC8 and associated to Cornelia de Lange syndrome 5. By molecular modeling, the amino acid change compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, triggering global structural changes that propagate through the protein scaffold to the catalytic site, creating de facto haploinsufficiency. The effects observed are similar of those described by Decroos and colleagues regarding the p.Gly117Glu replacement, which compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, resulting in a 5% residual enzyme activity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at