Submissions for variant NM_004168.4(SDHA):c.136A>G (p.Lys46Glu)

gnomAD frequency: 0.00145  dbSNP: rs144599870

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000210526	SCV000266800	likely benign	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000250106	SCV000309989	likely benign	not specified		criteria provided, single submitter	clinical testing
Counsyl	RCV000410409	SCV000488780	uncertain significance	Paragangliomas 5	2016-06-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001705183	SCV000524521	likely benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23666964, 28546994, 26802149)
Ambry Genetics	RCV000569199	SCV000664575	likely benign	Hereditary cancer-predisposing syndrome	2020-07-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Genetic Services Laboratory, University of Chicago	RCV000250106	SCV002068209	uncertain significance	not specified	2019-01-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569199	SCV002527707	likely benign	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410409	SCV004045352	uncertain significance	Paragangliomas 5	2023-04-24	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000250106	SCV004804060	likely benign	not specified	2024-01-31	criteria provided, single submitter	clinical testing	Variant summary: SDHA c.136A>G (p.Lys46Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 1613182 control chromosomes, predominantly at a frequency of 0.0049 within the African or African-American subpopulation in the gnomAD database. This suggests that the variant is very likely a benign polymorphism found primarily in populations of African or African-American origin. c.136A>G has been reported in the literature in at-least one individual affected with abdominal a paraganglioma (example: Casey_2017). This report does not provide unequivocal conclusions about association of the variant with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28546994). ClinVar contains an entry for this variant (Variation ID: 224951). Based on the evidence outlined above, the variant was classified as likely benign.