chr5-240396-G-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004168.4(SDHA):c.1471G>T(p.Glu491*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,609,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004168.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- pheochromocytoma/paraganglioma syndrome 5Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- mitochondrial complex II deficiency, nuclear type 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- neurodegeneration with ataxia and late-onset optic atrophyInheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
- Leigh syndromeInheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- gastrointestinal stromal tumorInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndrome with leukodystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial complex II deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy 1GGInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1471G>T | p.Glu491* | stop_gained | Exon 11 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1471G>T | p.Glu491* | stop_gained | Exon 11 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.*204G>T | non_coding_transcript_exon_variant | Exon 10 of 24 | ENSP00000499215.1 | |||||
ENSG00000286001 | ENST00000651543.1 | n.*204G>T | 3_prime_UTR_variant | Exon 10 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000400 AC: 1AN: 249978 AF XY: 0.00000738 show subpopulations
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1457690Hom.: 0 Cov.: 29 AF XY: 0.00000827 AC XY: 6AN XY: 725366 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74360 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23109135) -
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Pheochromocytoma/paraganglioma syndrome 5 Pathogenic:1
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Dilated cardiomyopathy 1GG Pathogenic:1
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Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Glu491*) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (rs778207102, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 472289). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.E491* pathogenic mutation (also known as c.1471G>T), located in coding exon 11 of the SDHA gene, results from a G to T substitution at nucleotide position 1471. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1
Variant summary: SDHA c.1471G>T (p.Glu491X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 249978 control chromosomes. c.1471G>T has been reported in the literature in at least one individual affected with paraganglioma (example: Ding_2022). The following publication has been ascertained in the context of this evaluation (PMID: 35546442). ClinVar contains an entry for this variant (Variation ID: 472289). Based on the evidence outlined above, the variant was classified as pathogenic. -
SDHA-related disorder Pathogenic:1
The SDHA c.1471G>T variant is predicted to result in premature protein termination (p.Glu491*). This variant has been reported in an individual with osteosarcoma (Table S5 in Mirabello et al. 2020. PubMed ID: 32191290). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in SDHA are expected to be pathogenic. This variant has conflicting interpretations in ClinVar, with the majority being pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/472289/). We interpret c.1471G>T (p.Glu491*) as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at