chr5-218358-G-A
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_004168.4(SDHA):c.3G>A(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 0.000000763 in 1,310,054 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 (★★).
Frequency
Consequence
NM_004168.4 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.3G>A | p.Met1? | start_lost | 1/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.3G>A | p.Met1? | start_lost | 1/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 7.63e-7 AC: 1AN: 1310054Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1AN XY: 646954
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | 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 autosomal recessive complex II deficiency, gastrointestinal stromal tumor and renal cell carcinoma, and/or paraganglioma (PMID: 24096523, 26642834, 26722403, 28384794; Invitae). ClinVar contains an entry for this variant (Variation ID: 2562379). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2023 | The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the SDHA gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). 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. - |
Paragangliomas 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 06, 2024 | 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: 35014173, 28384794, 10746566, 26722403, 32971818]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.