5-240459-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004168.4(SDHA):c.1534C>T(p.Arg512Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000673 in 1,605,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R512R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

SDHA
NM_004168.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 2.66

Variant links:

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

SDHA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-240459-C-T is Pathogenic according to our data. Variant chr5-240459-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-240459-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1534C>T	p.Arg512Ter	stop_gained	11/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.1534C>T	p.Arg512Ter	stop_gained	11/15	1	NM_004168.4	P1	P31040-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

250148

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135514

show subpopulations

Gnomad AFR exome

AF:

0.0000637

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000695

AC:

101

AN:

1453566

Hom.:

Cov.:

AF XY:

0.0000746

AC XY:

AN XY:

723510

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000823

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2022	Nonsense variant predicted to result in protein truncation or 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); Identified in patients with personal and family history consistent with pathogenic variants in this gene (Wagner 2013, Papathomas 2015, Maniam 2018, van der Tuin 2018, Ben Aim 2019); This variant is associated with the following publications: (PMID: 22955521, 25720320, 27011036, 28768491, 28546994, 24886695, 28748451, 23730622, 29978154, 31589614, 30877234, 31981491, 29177515, 32581362) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 25, 2022	PP4, PVS1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	SDHA: PVS1 -

Paragangliomas 5

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 21, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 11, 2021	The SDHA c.1534C>T (p.Arg512Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg512Ter variant has been reported in two studies in which it was identified as a germline variant in at least two affected individuals including one individual with a paraganglioma and one individual with a gastrointestinal stromal tumor (Wagner et al. 2013; Papathomas et al. 2015). The p.Arg512Ter variant is reported at a frequency of 0.000078 in the European (non-Finnish) population from of the Genome Aggregation Database. This allele frequency is high but is may be consistent with reduced penetrance. Based on the available evidence and application of the ACMG criteria, the p.Arg512Ter variant is classified as pathogenic for hereditary pheochromocytoma-paraganglioma syndrome. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 29, 2021	The p.R512* pathogenic mutation (also known as c.1534C>T), located in coding exon 11 of the SDHA gene, results from a C to T substitution at nucleotide position 1534. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been reported in both the germline and in the tumor of an individual with an extra-adrenal paraganglioma and in the germline of an individual with a testis paraganglioma (Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; van der Tuin K et al. J. Clin. Endocrinol. Metab. 2018 02;103(2):438-445). In another study, the mutation was carried by a 53-year-old female with metastatic retroperitoneal paraganglioma (Jha A et al. Front Oncol, 2019 Feb;9:53). This mutation has also been identified in several individuals with SDHA-deficient gastrointestinal stromal tumors (Wagner AJ et al. Mod Pathol, 2013 Feb;26:289-94; Jha A et al. Front Oncol, 2019 Feb;9:53). In addition to the clinical data presented in the literature, 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. -

Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

Opsoclonus-myoclonus syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe

- -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change creates a premature translational stop signal (p.Arg512*) 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 (rs748089700, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with paraganglioma and/or gastrointestinal stromal tumor (PMID: 22955521, 25720320). ClinVar contains an entry for this variant (Variation ID: 371805). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1GG

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 21, 2023

- -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2022

The p.Arg512X variant in SDHA has been reported in 5 individuals with SDHA-related tumors (paragangliomas, pheochromocytomas, GISTs) and segregated with disease in 2 affected individuals from 2 families (Wagner 2013 PMID: 22955521, Papathomas 2015 PMID: 25720320, van der tuin 2018 PMID: 29177515, Ben Aim 2019 PMID: 30877234, Whitworth 2021 PMID: 33854214). It has also been identified in 0.009% (6/68038) of European chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 371805). This nonsense variant leads to a premature termination codon at position 512, which is predicted to lead to a truncated or absent protein. Loss of function of the SDHA gene is an established disease mechanism in autosomal dominant Hereditary paraganglioma-pheochromocytoma syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Hereditary paraganglioma-pheochromocytoma. ACMG/AMP Criteria applied: PS4, PVS1, PM2_P. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.89

MutationTaster

Benign

1.0

A;A;A

Vest4

0.97

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over