Submissions for variant NM_004168.4(SDHA):c.1979C>G (p.Ala660Gly)

gnomAD frequency: 0.00013  dbSNP: rs191412461

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227636	SCV000288127	likely benign	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2025-02-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000409751	SCV000488533	uncertain significance	Paragangliomas 5	2016-04-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563763	SCV000674932	benign	Hereditary cancer-predisposing syndrome	2014-11-17	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.
CeGaT Center for Human Genetics Tuebingen	RCV000998351	SCV001154364	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001158017	SCV001319630	uncertain significance	Leigh syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001158018	SCV001319631	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001158019	SCV001319632	benign	Hereditary pheochromocytoma-paraganglioma	2017-05-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000998351	SCV001811315	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Reported in an individual with a paraganglioma (PMID: 28384794); This variant is associated with the following publications: (PMID: 28384794)
Sema4, Sema4	RCV000563763	SCV002527740	likely benign	Hereditary cancer-predisposing syndrome	2021-09-27	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000998351	SCV003819236	uncertain significance	not provided	2019-07-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409751	SCV004018614	likely benign	Paragangliomas 5	2023-04-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000998351	SCV004220293	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with adrenal pheochromocytoma (PMID: 28384794 (2017)). The frequency of this variant in the general population, 0.00028 (10/35440 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV000998351	SCV005410664	uncertain significance	not provided	2024-06-24	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000998351	SCV001550126	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SDHA p.Ala579Gly variant was identified in dbSNP (ID: rs191412461), Clinvitae, LOVD 3.0 and ClinVar (reported as a variant of uncertain significance by Invitae and Counsyl and benign by Ambry Genetics) but was not found in Cosmic. The variant was identified in control databases in 35 of 282590 chromosomes at a frequency of 0.000124 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 10 of 35440 chromosomes (freq: 0.000282), European (non-Finnish) in 23 of 128896 chromosomes (freq: 0.000178), Other in 1 of 7220 chromosomes (freq: 0.000139) and African in 1 of 24970 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. This variant was identified in 1/972 heterozygous patients from the European-American-Asian Pheochromocytoma-Paraganglioma Registry (Bausch_2017_PMID: 28384794). The p.Ala579 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
PreventionGenetics, part of Exact Sciences	RCV004529398	SCV004110938	uncertain significance	SDHA-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The SDHA c.1979C>G variant is predicted to result in the amino acid substitution p.Ala660Gly. This variant was reported in an individual with adrenal paraganglioma (eTable 1 - Bausch et al. 2017. PubMed ID: 28384794). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity ranging from benign to uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/239660/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.