ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.143A>T (rs202101384)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470589 SCV000553986 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 48 of the SDHB protein (p.Asp48Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs202101384, ExAC 0.04%). This variant has been observed as homozygous or in combination with other SDHB variant in individuals affected with autosomal recessive mitochondrial complex II deficiency (PMID: 22972948, 26642834, 26925370, 27604842). However, this variant has not been observed in individuals with pheochromocytoma (PCC) or paraganglioma (PGL). ClinVar contains an entry for this variant (Variation ID: 39584). An experimental study showed that an equivalent missense change in yeast (p.Asn42Val) demonstrates a 50% reduction in succinate dehydrogenase activity, but similar oxidative growth and respiration compared to the humanized wild-type variant (p.Asn42Asp) (PMID: 22972948). Another experimental study showed impaired complex II enzyme activity and SDHB expression in patient-derived cells, though the clinical significance of this result is unclear because lymphocytes derived from an unaffected homozygous sibling showed similarly decreased SDHB expression (PMID: 26925370). In summary, this variant has been observed in individuals with mitochondrial complex II deficiency and has been shown to affect protein function. The currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. However, the association of this variant with hereditary PCC-PGL is currently unclear.
Ambry Genetics RCV001011583 SCV001171920 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing The p.D48V variant (also known as c.143A>T), located in coding exon 2 of the SDHB gene, results from an A to T substitution at nucleotide position 143. The aspartic acid at codon 48 is replaced by valine, an amino acid with highly dissimilar properties. This alteration has been detected in in both a homozygous and compound heterozygous state with a second SDHB alteration in multiple individuals with features of mitochondrial complex II deficiency (Alston CL et al. J. Med. Genet., 2012 Sep;49:569-77; Grønborg S et al. JIMD Rep, 2017 Sep;33:69-77; Helman G et al. Ann. Neurol., 2016 Mar;79:379-86;Vanderver A et al. Ann. Neurol., 2016 Jun;79:1031-7; Ardissone A et al. Mol Genet Metab Rep, 2015 Dec;5:51-54). However, this alteration has not to date been reported in the literature in individuals with pheochromocytomas or paragangliomas. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
OMIM RCV000032784 SCV000056548 pathogenic Mitochondrial complex 2 deficiency, nuclear type 4 2012-09-01 no assertion criteria provided literature only
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, RCV001249469 SCV001370765 uncertain significance Mitochondrial complex II deficiency, nuclear type 1 no assertion criteria provided clinical testing
GeneDx RCV001578167 SCV001805706 pathogenic not provided 2018-10-30 no assertion criteria provided clinical testing This variant has only been reported/observed in association with autosomal recessive complex II deficiency and has not, to our knowledge, been associated with autosomal dominant hereditary paraganglioma/pheochromocytoma syndrome; This variant is associated with the following publications: (PMID: 31589614, 26925370, 29019354, 23174333, 27604842, 26968897, 22972948, 27159321, 26642834, 29282712, 27556822)

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