chr5-236598-TGG-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004168.4(SDHA):c.1432_1432+1delGG(p.Gly478fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004168.4 frameshift, splice_donor, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1432_1432+1delGG | p.Gly478fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | 10/15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1432_1432+1delGG | p.Gly478fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | 10/15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.*165_*165+1delGG | splice_region_variant, non_coding_transcript_exon_variant | 9/24 | ENSP00000499215.1 | |||||
ENSG00000286001 | ENST00000651543.1 | n.*165_*165+1delGG | splice_donor_variant, 3_prime_UTR_variant, intron_variant | 9/24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251166Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135740
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000376 AC: 55AN: 1461504Hom.: 0 AF XY: 0.0000454 AC XY: 33AN XY: 727066
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 11, 2022 | - - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This variant results in the deletion of part of exon 10 (c.1432_1432+1del) of the SDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with breast cancer, paraganglioma-pheochromocytoma syndrome, and/or renal cancer (PMID: 29177515, 30877234, 32782288, 34750850; Invitae). ClinVar contains an entry for this variant (Variation ID: 239647). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Dilated cardiomyopathy 1GG Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 07, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2023 | Canonical splice site variant predicted to result in a null allele 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: 24781757, 22974104, 31263571, 16199547, 30877234, 29177515, 26556299, 34750850, 32782288, 35053433) - |
Paraganglioma;C0031511:Pheochromocytoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Cancer Variant Interpretation Group UK, Institute of Cancer Research, London | Jul 10, 2020 | This variant has been observed in a male proband with phaeochromocytoma and lung nodule. The variant has previously been reported in the literature, including in a male with glomus jugulare tumour (PMID: 29177515); a male with retroperitoneal paraganglioma (PMID 28384794); a male with gallbladder paraganglioma, pancreatic neuroendocrine tumour and metastatic prostate cancer (PMID: 32534711); and a female with thoracic paraganglioma (PMCID: PMC7209502) (PS4_moderate). The variant is absent from population database gnomAD (PM2_supporting) and is predicted to result in loss of protein function (PVS1_very_strong). Data included in classification: Prevalence in affected versus controls GT-AG 1,2 splice site variant predicted to result in loss of protein function Data not included in classification: Functional data - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2023 | The c.1432_1432+1delGG pathogenic mutation spans the coding exon 10/intron 10 boundary of the SDHA gene and results from the deletion of 2 nucleotides at nucleotide positions c.1432 and c.1432+1. The deleted region includes the last nucleotide and canonical donor site, which is highly conserved in available vertebrate species. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHA-related disease (Ambry internal data; Bausch B et al. JAMA Oncol 2017 Sep;3(9):1204-1212; van der Tuin K et al. J Clin Endocrinol Metab 2018 02;103(2):438-445). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 04, 2023 | Variant summary: SDHA c.1432_1432+1delGG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251166 control chromosomes (gnomAD). c.1432_1432+1delGG has been reported in the literature in individuals affected with paraganglioma or cancers including renal cancer (van der Tuin_2018, Ben Aim_2019, Hartman_2020, Parisien-La Salle_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29177515, 30877234, 34750850, 32782288). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Paragangliomas 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 08, 2024 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at