ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.143A>T (p.Asp48Val) (rs202101384)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470589 SCV000553986 likely pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-12-27 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.
OMIM RCV000032784 SCV000056548 uncertain significance Variant of unknown significance 2012-09-01 no assertion criteria provided literature only

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