chr11-112094969-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM4PP5
The NM_003002.4(SDHD):c.479G>T(p.Ter160LeuextTer3) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,610,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. *160*) has been classified as Likely benign.
Frequency
Consequence
NM_003002.4 stop_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHD | NM_003002.4 | c.479G>T | p.Ter160LeuextTer3 | stop_lost | 4/4 | ENST00000375549.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHD | ENST00000375549.8 | c.479G>T | p.Ter160LeuextTer3 | stop_lost | 4/4 | 1 | NM_003002.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247668Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134696
GnomAD4 exome AF: 0.00000823 AC: 12AN: 1458320Hom.: 0 Cov.: 29 AF XY: 0.00000827 AC XY: 6AN XY: 725576
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2023 | Published functional studies demonstrate a damaging effect: reduced enzyme activities of the individual respiratory chains complexes in skeletal muscle and inability to restore the complex II assembly in a fibroblast cell line (Jackson et al., 2014); Normal stop codon changed to a Leucine codon, leading to the addition of 3 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.X104LextX3; This variant is associated with the following publications: (PMID: 24367056, 34012134, 33162331) - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 20, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Extension variant reported in 1 proband with autosomal recessive encephalomyopathy and MT complex II deficiency - proband carried E69K on other allele. Complementation of a patient cell line supported the pathogenicity of the SDHD variants. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 04, 2018 | Variant summary: SDHD c.479G>T (p.X160LeuextX3) changes the termination codon and is predicted to lead to an extended protein with additional 3 amino acids added to the normal C-terminus. The variant allele was found at a frequency of 4.1e-06 in 242834 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.479G>T has been reported in the literature in one individual affected with mitochondrial complex II deficiency in compound heterozygous state (Jackson_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about causality of the variant (Jackson_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary pheochromocytoma-paraganglioma Uncertain:2
Uncertain significance, no assertion criteria provided | research | Section on Medical Neuroendocrinolgy, National Institutes of Health | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This variant is a termination codon variant that changes the translational stop signal of the SDHD gene to leucine and extends the length of the SDHD protein by 3 additional amino acids. A functional complementation experiment using patient fibroblasts harboring the SDHD c.205G>A p.(Glu69Lys) and SDHD c.479G>T p.*160Leuext*3 variants demonstrated that transduction with either mutant transcript was unable to rescue the reduced expression and activity of the succinate dehydrogenase complex, whereas transduction of the patient fibroblasts with the wild type SDHD cDNA transcript restored SDH activity. Mitochondrial complex II activity and levels were also significantly reduced in patient cells (PMID: 24367056). This variant has been reported in trans with another SDHD variant (c.205G>A, p.Glu69Lys) in a single individual with autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency (PMID: 24367056). The parents were heterozygous for one of the variants each and have been referred for tumor surveillance. Screening with 24 h measurements of blood pressure and urinary catecholamines of both parents was normal. The SDHD / c.479G>T / p.160Leuext3 variant has been observed in two individuals with paraganglioma at NIH (ClinVar, SCV000599548.1, personal communication). A similar stop loss variant in the SDHD gene, (c.479_480insGT, p.*160Trpext*8) has been identified in a patient with bilateral carotid paragangliomas (PMID: 31508186). The SDHD c.479G>T p.*160Leuext*3 variant has been identified in 1/247668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While the evidence may support a causal role in autosomal recessive mitochondrial complex II deficiency, the clinical significance with respect to autosomal dominant paraganglioma-pheochromocytoma syndrome is uncertain. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Mitochondrial complex 2 deficiency, nuclear type 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2024 | The c.479G>T variant (also known as p.*160Lext*3), located in coding exon 4 of the SDHD gene, results from a G to T substitution at nucleotide position 479, which is the second to last nucleotide of the SDHD gene. This alteration disrupts the stop codon of the SDHD gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 3 amino acids. The exact functional effect of the additional amino acids is unknown. This alteration has been reported as compound heterozygous with a second SDHD alteration, p.E69K, in an individual with autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency (Jackson CB et al. J. Med. Genet., 2014 Mar;51:170-5). Functional studies demonstrated that the introduction of this variant to patient cells was unable to recover complex II formation compared to a WT control (Jackson CB et al. J. Med. Genet., 2014 Mar;51:170-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive mitochondrial complex II deficiency when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the clinical significance in regards to paraganglioma-pheochromocytoma syndrome is unlikely. - |
Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change disrupts the translational stop signal of the SDHD mRNA. It is expected to extend the length of the SDHD protein by 3 additional amino acid residues. This variant is present in population databases (rs201372601, gnomAD 0.0009%). This protein extension has been observed in individual(s) with mitochondrial complex II deficiency (PMID: 24367056). ClinVar contains an entry for this variant (Variation ID: 156154). 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 this protein extension affects SDHD function (PMID: 24367056). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at