rs370690436
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5
The NM_004168.4(SDHA):c.1352G>A(p.Arg451His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R451C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1352G>A | p.Arg451His | missense_variant | 10/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1352G>A | p.Arg451His | missense_variant | 10/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152258Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251174Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135744
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461670Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727146
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74390
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2024 | The p.R451H variant (also known as c.1352G>A), located in coding exon 10 of the SDHA gene, results from a G to A substitution at nucleotide position 1352. The arginine at codon 451 is replaced by histidine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHA-related disease (Toledo RA et al. Clin Cancer Res, 2016 05;22:2301-10; Bannon AE et al. Clin Cancer Res, 2017 Nov;23:6733-6743; van der Tuin K et al. J Clin Endocrinol Metab, 2018 02;103:438-445; Ambry internal data). In one study, the R451H variant was unable to grow on glycerol as carbon source, had decreased oxygen consumption and decreased Sdh2 protein. Computational modeling showed this variant disrupts flavin binding, succinate binding, and proton shuttle necessary for catalytic activity (Bannon AE et al. Clin Cancer Res, 2017 Nov;23:6733-6743). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 03, 2021 | - - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 451 of the SDHA protein (p.Arg451His). This variant is present in population databases (rs370690436, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma and pheochromocytoma (PMID: 26700204, 29177515; Invitae). ClinVar contains an entry for this variant (Variation ID: 581412). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. Experimental studies have shown that this missense change affects SDHA function (PMID: 28724664). For these reasons, this variant has been classified as Pathogenic. - |
Dilated cardiomyopathy 1GG Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | KTest Genetics, KTest | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at