5-218356-A-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_004168.4(SDHA):āc.1A>Cā(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,298 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 Pathogenic (ā ā ).
Frequency
Consequence
NM_004168.4 initiator_codon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.1A>C | non_coding_transcript_exon_variant | Exon 1 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000382 AC: 5AN: 1308140Hom.: 0 Cov.: 31 AF XY: 0.00000310 AC XY: 2AN XY: 645810
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74324
ClinVar
Submissions by phenotype
Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
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Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
This sequence change affects the initiator methionine of the SDHA mRNA. The next in-frame methionine is located at codon 114. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with pheochromocytoma, gastrointestinal stromal tumor, and clinical features of complex II deficiency (PMID: 10746566, 28384794, 31413764). ClinVar contains an entry for this variant (Variation ID: 8744). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SDHA function (PMID: 10746566). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.M1? pathogenic mutation (also known as c.1A>C) is located in coding exon 1 of the SDHA gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. There is an in-frame methionine 114 amino acids downstream from this initiation site which may result in an N-terminal truncation; however, direct evidence is unavailable. This alteration has been reported in an individual with Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43). This alteration has also been observed individuals with paraganglioma and gastrointestinal stromal tumor (GIST) (Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212; Carrera S et al. Hered. Cancer Clin. Pract. 2019 Aug;17:23). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1
Variant summary: SDHA c.1A>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame Methionine is located at codon 114 in exon 4 of the encoded protein sequence. The variant was absent in 114846 control chromosomes. c.1A>C has been reported in the literature as a compound heterozygous genotype in an individual affected with features of Leigh Syndrome with Succinate dehydrogenase deficiency (example, Parfait_2000) and as a heterozygous genotype in individuals affected with features of extra-adrenal thoracid paraganglioma and/or Gastrointestinal stromal tumors (GISTs) (example, Bausch_2017, Carrera_2019). At least one publication reports experimental evidence evaluating an impact on transcript levels (Parfait_2000). The most pronounced variant effect results in mutant transcript representing only 10% of total Flavoprotein (Fp) transcripts, suggesting a high instability of this transcript. The following publications have been ascertained in the context of this evaluation (PMID: 28384794, 31413764, 10746566). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Paragangliomas 5 Pathogenic:1
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28384794, 35014173, 10746566, 32971818]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at