rs121908538
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003850.3(SUCLA2):c.850C>T(p.Arg284Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R284R) has been classified as Likely benign.
Frequency
Consequence
NM_003850.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUCLA2 | NM_003850.3 | c.850C>T | p.Arg284Cys | missense_variant | 7/11 | ENST00000646932.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUCLA2 | ENST00000646932.1 | c.850C>T | p.Arg284Cys | missense_variant | 7/11 | NM_003850.3 | P1 | ||
ENST00000657958.1 | n.59-1337G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152046Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250822Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135552
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461566Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727086
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74270
ClinVar
Submissions by phenotype
Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jan 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 284 of the SUCLA2 protein (p.Arg284Cys). This variant is present in population databases (rs121908538, gnomAD 0.01%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 17301081, 28749033, 30315573, 32718099). ClinVar contains an entry for this variant (Variation ID: 5978). 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 SUCLA2 protein function with a positive predictive value of 80%. Studies have shown that this missense change alters SUCLA2 gene expression (PMID: 17301081). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2007 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 17301081, 32718099, 30315573, 34440436, 28749033) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at