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

Total submissions: 8

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