Submissions for variant NM_004168.4(SDHA):c.1919A>G (p.Glu640Gly)

gnomAD frequency: 0.00058  dbSNP: rs372480044

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000239361	SCV000297689	likely benign	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574591	SCV000664530	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-29	criteria provided, single submitter	clinical testing	The p.E640G variant (also known as c.1919A>G), located in coding exon 15 of the SDHA gene, results from an A to G substitution at nucleotide position 1919. The glutamic acid at codon 640 is replaced by glycine, an amino acid with similar properties. This alteration was detected in a large Brazilian family with multiple cases of papillary thyroid cancer, but it did not segregate with disease (Accordi ED et al. Eur Thyroid J. 2016 Jul;5:94-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Counsyl	RCV000663177	SCV000786344	uncertain significance	Paragangliomas 5	2018-04-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765835	SCV000897230	uncertain significance	Leigh syndrome; Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000836807	SCV000978653	likely benign	not provided	2019-12-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17376234, 27493882, 31376648)
Sema4, Sema4	RCV000574591	SCV002527736	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663177	SCV004018601	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586651	SCV005076962	uncertain significance	not specified	2024-04-08	criteria provided, single submitter	clinical testing	Variant summary: SDHA c.1919A>G (p.Glu640Gly) results in a non-conservative amino acid change located in the Fumarate reductase/succinate dehydrogenase flavoprotein-like, C-terminal domain (IPR015939) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251168 control chromosomes in the gnomAD database, including 1 homozygote. c.1919A>G has been reported in the literature in a family affected with Familiar Papillary Thyroid Carcinoma but did not segregate with disease (Accordi_2016). These report(s) do 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 have been ascertained in the context of this evaluation (PMID: 27493882). ClinVar contains an entry for this variant (Variation ID: 252908). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.