Submissions for variant NM_004168.4(SDHA):c.1064+5G>A

gnomAD frequency: 0.00006  dbSNP: rs200021115

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411854	SCV000488343	uncertain significance	Paragangliomas 5	2016-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466048	SCV000553885	likely benign	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2025-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561515	SCV000674929	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV001584106	SCV001819407	uncertain significance	not provided	2020-10-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Sema4, Sema4	RCV000561515	SCV002527692	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411854	SCV004018615	uncertain significance	Paragangliomas 5	2023-04-21	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001584106	SCV005624113	uncertain significance	not provided	2024-02-02	criteria provided, single submitter	clinical testing	The SDHA c.1064+5G>A variant has not been reported in individuals with SDHA-related conditions in the published literature. The frequency of this variant in the general population, 0.000085 (3/35440 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper SDHA mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.
Clinical Genomics Laboratory, Stanford Medicine	RCV000466048	SCV005873520	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2022-10-28	criteria provided, single submitter	clinical testing	The c.1064+5G>A variant in the SDHA gene has not been previously reported in association with disease. This variant has been identified in 2/19,954 East Asian chromosomes (17/282,696 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 371829).This variant occurs in the 5' donor splice site of intron 8. Computational splicing tools predict an impact to splicing; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the c.1064+5G>A variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3]