Submissions for variant NM_004168.4(SDHA):c.1471G>T (p.Glu491Ter)

gnomAD frequency: 0.00001  dbSNP: rs778207102

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000555437	SCV000651337	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu491*) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (rs778207102, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 472289). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000566587	SCV000664471	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	clinical testing	The p.E491* pathogenic mutation (also known as c.1471G>T), located in coding exon 11 of the SDHA gene, results from a G to T substitution at nucleotide position 1471. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Illumina Laboratory Services, Illumina	RCV000779471	SCV000916099	uncertain significance	SDHA-Related Disorders	2018-05-03	criteria provided, single submitter	clinical testing	The SDHA c.1471G>T (p.Glu491Ter) variant is a stop-gained variant. The p.Glu491Ter variant has been reported in a homozygous state in one gastrointestinal stromal tumor (GIST) sample from a single patient (Belinsky et al. 2013). SNP analysis suggested a loss of the wild type allele in the tumor through a copy number loss, but the genomic DNA was unavailable for analysis. Another individual affected with GIST was found to carry a stop-gained variant, p.Glu490Ter, at the adjacent amino acid position in an unknown zygosity (Casey et al. 2017). The p.Glu491Ter variant is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. The p.Glu491Ter variant has not been identified in patients with Leigh syndrome or mitochondrial respiratory chain complex II deficiency. Due to the potential impact of stop-gained variants and the limited clinical evidence, p.Glu491Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for SDHA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV001093472	SCV001250482	pathogenic	not provided	2018-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001093472	SCV003915091	likely pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23109135)
PreventionGenetics, part of Exact Sciences	RCV003409811	SCV004113431	pathogenic	SDHA-related condition	2022-12-08	criteria provided, single submitter	clinical testing	The SDHA c.1471G>T variant is predicted to result in premature protein termination (p.Glu491*). This variant has been reported in an individual with osteosarcoma (Table S5 in Mirabello et al. 2020. PubMed ID: 32191290). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-240511-G-T). Nonsense variants in SDHA are expected to be pathogenic. This variant has conflicting interpretations in ClinVar, with the majority being pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/472289/). We interpret c.1471G>T (p.Glu491*) as pathogenic.
Baylor Genetics	RCV003476303	SCV004200596	likely pathogenic	Dilated cardiomyopathy 1GG	2023-08-18	criteria provided, single submitter	clinical testing