5-218357-T-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.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000084 in 1,309,370 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 (ā ā ).
Frequency
Consequence
NM_004168.4 start_lost
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.2T>C | p.Met1? | start_lost | 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.2T>C | p.Met1? | start_lost | Exon 1 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.2T>C | non_coding_transcript_exon_variant | Exon 1 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes Cov.: 35
GnomAD3 exomes AF: 0.00000866 AC: 1AN: 115518Hom.: 0 AF XY: 0.0000150 AC XY: 1AN XY: 66786
GnomAD4 exome AF: 0.00000840 AC: 11AN: 1309370Hom.: 0 Cov.: 31 AF XY: 0.0000108 AC XY: 7AN XY: 646500
GnomAD4 genome Cov.: 35
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the SDHA gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This mutation has been reported in a 23-year-old individual with a GIST and a concurrent renal cell carcinoma and was not detected in 100 population-matched controls (Jiang Q et al. Int J Clin Exp Pathol 2015 Oct;8(10):12188-97). 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 alteration is interpreted as a disease-causing mutation. -
The SDHA:c.2T>C variant was detected rarely in gnomAD population databases. It is a null variant, resulting in a starting loss located in exon 1, which aligns with a known mechanism of disease. Additionally, it leads to the same amino acid change as a known pathogenic variant. This variant was detected in a 57-year-old Korean woman diagnosed with hormone-positive and invasive ductal breast cancer. She had a family history of first-degree relatives with breast cancer and pancreatic cancer. -
Paragangliomas 5 Pathogenic:2
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, 10746566, 26722403, 32971818]. -
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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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with GIST, paraganglioma and autosomal recessive mitochondrial complex II deficiency (PMID: 10746566, 26722403, 28384794; internal data). ClinVar contains an entry for this variant (Variation ID: 412398). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at