ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.479G>T (p.Ter160Leu) (rs201372601)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized 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 RCV000476218 SCV000554058 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-10-01 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 not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with encephalomyopathy and isolated mitochondrial complex II deficiency (PMID: 24367056). ClinVar contains an entry for this variant (Variation ID: 156154). Experimental studies have suggested that this variant results in a complex II assembly defect (PMID: 24367056). However, the clinical significance of this finding is unclear. 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, LabCorp 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000994727 SCV001148462 likely pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023072 SCV001184892 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 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. The stop codon at position 160 is replaced by Leucine, resulting in an elongation of the protein by 3 amino acids. This alteration has been reported as a mutation in conjunction with a second SDHD mutation, 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). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of SDHD, and is not expected to trigger nonsense-mediated mRNA decay. Since the exact functional impact of the inserted amino acids is unknown, and supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000994727 SCV001780853 likely pathogenic not provided 2020-07-27 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 a significant frequency in large population cohorts (Lek et al., 2016); Also known as p.X104LextX3; This variant is associated with the following publications: (PMID: 24367056)
OMIM RCV000144172 SCV000189249 pathogenic Mitochondrial complex 2 deficiency, nuclear type 3 2014-03-01 no assertion criteria provided literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505355 SCV000599548 uncertain significance Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.