5-218357-T-A
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_004168.4(SDHA):c.2T>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 0.00000153 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 35)
Exomes 𝑓: 0.0000015 ( 0 hom. )
Consequence
SDHA
NM_004168.4 start_lost
NM_004168.4 start_lost
Scores
3
5
8
Clinical Significance
Conservation
PhyloP100: 3.08
Genes affected
SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_004168.4 (SDHA) was described as [Pathogenic] in ClinVar as 1408872
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-218357-T-A is Pathogenic according to our data. Variant chr5-218357-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 582115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.2T>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.2T>A | p.Met1? | start_lost | 1/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 35
GnomAD3 genomes
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35
GnomAD3 exomes AF: 0.00000866 AC: 1AN: 115518Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 66786
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GnomAD4 exome AF: 0.00000153 AC: 2AN: 1309370Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 646500
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GnomAD4 genome Cov.: 35
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35
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2023 | This sequence change affects the initiator methionine of the SDHA mRNA. The next in-frame methionine is located at codon 114. This variant is present in population databases (rs750380279, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with gastrointestinal stromal tumor, renal cell carcinoma, paraganglioma, pheochromocytoma, and complex II deficiency (PMID: 10746566, 26334176, 26722403, 28384794). ClinVar contains an entry for this variant (Variation ID: 582115). Algorithms developed to predict the effect of variants on protein 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). Rescue of translational initiation by the downstream methionine would be expected to result in the disruption of the N-terminal part of the SDHA protein, which is important for FAD binding (PMID: 25488574, 15989954). This suggests that disruption of this region of the protein is causative of disease. 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 | Nov 16, 2020 | The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the SDHA gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). 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. Other alterations impacting the initiation codon (c.2T>C, c.2T>G, c.1A>C, c.1A>G) have been reported in individuals with personal history consistent with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, including gastrointestinal stromal tumor (GIST), renal cell carcinoma, and carotid paraganglioma (Jiang Q et al. Int J Clin Exp Pathol 2015 Oct;8(10):12188-97; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Carrera S et al. Hered. Cancer Clin. Pract. 2019 Aug;17:23). Further, the c.1A>C alteration impacting the SDHA initiation codon has been observed in an individual with autosomal recessive Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43). 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. | Jan 12, 2023 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PROVEAN
Benign
.;N;N;N
REVEL
Uncertain
Sift
Uncertain
.;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
0.32, 0.21
.;B;B;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0061);Gain of catalytic residue at M1 (P = 0.0061);Gain of catalytic residue at M1 (P = 0.0061);Gain of catalytic residue at M1 (P = 0.0061);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at