5-228228-TG-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004168.4(SDHA):βc.667delGβ(p.Asp223IlefsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000131 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004168.4 frameshift
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.667delG | p.Asp223IlefsTer3 | frameshift_variant | Exon 6 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.667delG | p.Asp223IlefsTer3 | frameshift_variant | Exon 6 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.667delG | non_coding_transcript_exon_variant | Exon 6 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251164Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135740
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000753 AC: 11AN: 1461560Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727112
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
not provided Pathogenic:3
SDHA: PVS1, PM2 -
Frameshift 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; This variant is associated with the following publications: (PMID: 28152038, 31589614, 29778030, 29177515) -
This frameshift variant alters the translational reading frame of the SDHA mRNA and causes the premature termination of SDHA protein synthesis. The frequency of this variant in the general population, 0.00017 (6/35438 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an individual with paragangliomas (PMID: 29177515 (2018)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
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The c.667delG pathogenic mutation, located in coding exon 6 of the SDHA gene, results from a deletion of one nucleotide at nucleotide position 667, causing a translational frameshift with a predicted alternate stop codon (p.D223Ifs*3). This variant has been reported in a Dutch patient diagnosed with bilateral glomus vagal tumors and a glomus carotid body tumor at age 49 (van der Tuin K et al. J Clin Endocrinol Metab, 2018 02;103:438-445). This nucleotide position is highly conserved in available vertebrate species. 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. -
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp223Ilefs*3) 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 (rs779126007, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with a carotid body tumor and bilateral glomus vagal tumors (PMID: 29177515). ClinVar contains an entry for this variant (Variation ID: 141876). For these reasons, this variant has been classified as Pathogenic. -
Dilated cardiomyopathy 1GG Pathogenic:1
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SDHA-related disorder Pathogenic:1
The SDHA c.667delG variant is predicted to result in a frameshift and premature protein termination (p.Asp223Ilefs*3). This variant was reported in an individual with a carotid body tumor and bilateral glomus vagal tumors (van der Tuin K et al 2018. PubMed ID: 29177515). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and has been interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141876/). Frameshift variants in SDHA are expected to be pathogenic. This variant is interpreted as pathogenic. -
Paragangliomas 5 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at