ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1367C>T (p.Ser456Leu)

gnomAD frequency: 0.00001  dbSNP: rs76896145
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000649467 SCV000771295 benign Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2024-01-31 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001354634 SCV002009962 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002386098 SCV002702214 benign Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354634 SCV001549298 uncertain significance not provided no assertion criteria provided clinical testing The SDHA p.Ser408Leu variant was not identified in the literature or in the Cosmic database but was identified in dbSNP (ID: rs76896145), ClinVar (reported as benign by Invitae for mitochondrial complex II deficiency and paragangliomas 5) and LOVD 3.0. The variant was identified in control databases in 21 of 273542 chromosomes at a frequency of 0.000077 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24354 chromosomes (freq: 0.000164), European (non-Finnish) in 16 of 123988 chromosomes (freq: 0.000129) and South Asian in 1 of 28962 chromosomes (freq: 0.000035); it was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Ser408 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, and MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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