5-224432-C-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.223C>T(p.Arg75*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,508 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 (★★). 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
Genome browser will be placed here
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.223C>T | p.Arg75* | stop_gained | Exon 3 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.223C>T | p.Arg75* | stop_gained | Exon 3 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.223C>T | non_coding_transcript_exon_variant | Exon 3 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000916 AC: 23AN: 251178 AF XY: 0.000103 show subpopulations
GnomAD4 exome AF: 0.0000705 AC: 103AN: 1461290Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 726950 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74374 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Pheochromocytoma/paraganglioma syndrome 5 Pathogenic:3
PVS1, PS4, PP5, BP5 -
- -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
not provided Pathogenic:3
- -
Nonsense variant predicted to result in protein truncation or 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); This variant is associated with the following publications: (PMID: 32255556, 28500238, 27899191, 24694336, 27159395, 29978154, 28384794, 30877234, 33726816, 32570879, 23750034) -
This nonsense variant causes the premature termination of SDHA protein synthesis. The frequency of this variant in the general population, 0.00065 (17/26134 chromosomes in Swedish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. However, in the published literature, this variant is reported as being associated with reduced penetrance of developing cancer (PMID: 29978154 (2018)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32570879 (2020)), pancreatic ductal adenocarcinoma (PDAC) (PMID: 32255556 (2020)), and hereditary paraganglioma-pheochromocytoma (PGL-PCC) (PMIDs: 30877234 (2019), 24694336 (2014), 23750034 (2013)). Based on the available information, this variant is classified as pathogenic. -
Dilated cardiomyopathy 1GG Pathogenic:1
- -
Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg75*) 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 (rs781764920, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with paraganglioma and/or pheochromocytoma (PMID: 23750034, 24694336). ClinVar contains an entry for this variant (Variation ID: 209127). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.R75* pathogenic mutation (also known as c.223C>T), located in coding exon 3 of the SDHA gene, results from a C to T substitution at nucleotide position 223. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was reported in a woman with a paraganglioma diagnosed at age 20 (Welander J et al. J. Clin. Endocrinol. Metab., 2013 Aug;98:E1379-80) and in a male diagnosed with pheochromocytoma at 47 (Welander J et al. J Clin Endocrinol Metab, 2014 Jul;99:E1352-60). This mutation has also been identified in individuals with spindle cell breast cancer and pancreatic cancer (Sprissler R et al. Cancers (Basel), 2020 Jun;12; Cremin C et al. Cancer Med, 2020 06;9:4004-4013). In addition to the clinical data presented in the literature, 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. -
Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at