Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000454533 | SCV000540308 | uncertain significance | not specified | 2016-10-20 | criteria provided, single submitter | clinical testing | 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. |
Invitae | RCV002228513 | SCV000554058 | uncertain significance | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 | 2024-01-21 | criteria provided, single submitter | clinical testing | 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000454533 | SCV000918203 | uncertain significance | not specified | 2018-12-04 | criteria provided, single submitter | clinical testing | 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. |
Ce |
RCV000994727 | SCV001148462 | likely pathogenic | not provided | 2019-04-01 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001023072 | SCV001184892 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-15 | criteria provided, single submitter | clinical testing | 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 mitochondrial complex II deficiency; however, the clinical significance in regards to paraganglioma-pheochromocytoma syndrome remains unclear. |
Gene |
RCV000994727 | SCV001780853 | likely pathogenic | not provided | 2023-08-26 | criteria provided, single submitter | clinical testing | 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) |
OMIM | RCV000144172 | SCV000189249 | pathogenic | Mitochondrial complex 2 deficiency, nuclear type 3 | 2014-03-01 | no assertion criteria provided | literature only | |
Section on Medical Neuroendocrinolgy, |
RCV000505355 | SCV000599548 | uncertain significance | Hereditary pheochromocytoma-paraganglioma | no assertion criteria provided | research |