ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.133G>A (p.Ala45Thr) (rs140736646)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000210508 SCV000266796 uncertain significance Mitochondrial complex II deficiency; Paragangliomas 5 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 45 of the SDHA protein (p.Ala45Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs140736646, ExAC 0.09%). This variant has been reported in an individual with a single thoracic paraganglioma (PMID: 28546994). ClinVar contains an entry for this variant (Variation ID: 224947). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV000401643 SCV000456974 uncertain significance Mitochondrial complex II deficiency 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000308179 SCV000456975 uncertain significance Leigh syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000347454 SCV000456976 uncertain significance Pheochromocytoma 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000410936 SCV000488388 uncertain significance Paragangliomas 5 2016-03-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572294 SCV000664501 likely benign Hereditary cancer-predisposing syndrome 2019-05-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Arora Lab,Fox Chase Cancer Center RCV000678682 SCV000693859 uncertain significance Hereditary renal cell carcinoma 2018-02-26 no assertion criteria provided research The p.Ala45Thr variant (rs140736646) was found by exome sequencing in two siblings affected by renal cancer. While this variant is most prevalent in Europeans (97/126426 in the ExAC dataset (Lek et al., 2016)), it was inherited from the mother who also carried, in homozygous state, non-rare SDHA variants linked to African ancestry. The SDHA protein is a nuclear encoded mitochondrial protein, synthesized with a cleavage pre-sequence (residues 1 to 42) and imported to the matrix through the presequence cleavage pathway. The residue 45 in the preprotein becomes residue 3 in the mature protein, which assembles into the SDH complex. Scores of pathogenicity are low but may not take into account possible effects of the substitution on the different steps of the presequence processing. Immunostaining of the renal tumor of one of the siblings showed reduction in SDHA and loss of SDHB. This is expected from SDHA deficient tumors but could result from other events. As this single case study is insufficient to conclude for pathogenicity, this variant is classified as VUS.

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