Submissions for variant NM_004168.4(SDHA):c.969C>T (p.Gly323=)

gnomAD frequency: 0.00430  dbSNP: rs142849100

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129664	SCV000184462	benign	Hereditary cancer-predisposing syndrome	2014-11-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV000203785	SCV000262485	benign	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000246464	SCV000310008	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000362684	SCV000457019	likely benign	Leigh syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000399972	SCV000457020	benign	Hereditary pheochromocytoma-paraganglioma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000314076	SCV000457021	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000246464	SCV000518991	benign	not specified	2016-03-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago	RCV000246464	SCV002069746	benign	not specified	2021-03-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129664	SCV002527781	benign	Hereditary cancer-predisposing syndrome	2020-08-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000246464	SCV002550445	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000246464	SCV002773967	benign	not specified	2021-07-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001357190	SCV003799836	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315880	SCV004015391	benign	Paragangliomas 5	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001357190	SCV004151952	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SDHA: BP4, BP7, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357190	SCV001552576	likely benign	not provided		no assertion criteria provided	clinical testing	The SDHA p.Gly275Gly variant was not identified in the literature nor was it identified in the Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs142849100) as "With Likely benign allele". The variant was identified in ClinVar, classified as benign and likely benign. There are 7 submissions for this variant in ClinVar: 3 submissions of benign (Ambry Genetics, Invitae, and Prevention Genetics) and 4 submissions of likely benign (3 from Illumina and 1 from GeneDx). The variant was also identified in Clinvitae with one submission from Invitae of likely benign. The variant was identified in control databases in 1956 of 282892 chromosomes (23 homozygous) at a frequency of 0.006914 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 246 of 10370 chromosomes (freq: 0.02372), South Asian in 706 of 30616 chromosomes (freq: 0.02306), Other in 68 of 7228 chromosomes (freq: 0.009408), European (non-Finnish) in 782 of 129192 chromosomes (freq: 0.006053), Latino in 82 of 35440 chromosomes (freq: 0.002314), European (Finnish) in 44 of 25122 chromosomes (freq: 0.001751), African in 27 of 24970 chromosomes (freq: 0.001081) and East Asian in 1 of 19954 chromosomes (freq: 0.00005). The p.(Gly275Gly) variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, however 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. Computational evidence is only available from MutationTaster, and the variant is predicted to be disease causing. The Gly275 residue is conserved across mammals and other organisms. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000246464	SCV001807309	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001357190	SCV001951574	likely benign	not provided		no assertion criteria provided	clinical testing