chr5-218356-A-G

Position:

chr5-218356-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong

The NM_004168.4(SDHA):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000247 in 1,460,298 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 (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SDHA
NM_004168.4 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.636

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 18 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_004168.4 (SDHA) was described as [Pathogenic] in ClinVar as 1408872

PP5

Variant 5-218356-A-G is Pathogenic according to our data. Variant chr5-218356-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/15	1	NM_004168.4	P1	P31040-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152158

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:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000871

AC:

AN:

114846

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

66408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000172

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000214

AC:

AN:

1308140

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

645810

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000322

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000239

Gnomad4 OTH exome

AF:

0.0000374

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000136

AC:

ExAC

AF:

0.0000177

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 5

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Jun 06, 2018	This mutation was detected in a patient with bladder cancer in our cohort. While this genomic alteration meets ACMG criteria as pathogenic, additional features suggest this variant was driving the bladder cancer in the patient it was detected are lacking. A second hit was not observed in SDHA in the tumor and SDHA/B staining were retained in the tumor sample. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 15, 2022	The SDHA c.1A>G (p.Met1?) variant alters the initiator methionine amino acid and the resultant protein is described as p.Met1? to denote that whether the loss of the methionine at codon 1 prevents all protein translation or causes abnormal protein formation from an alternate methionine is unknown. This variant has been reported in a heterozygous state in an individual with pheochromocytoma (Davidoff et al. 2021) as well as individuals with bladder cancer (Dubart Gault et al. 2018; Carlo et al. 2020) and melanoma (Huang et al. 2018; Aoude et al. 2020). It has also been identified as a somatic variant in a tumor sample from an individual with a carotid paraganglioma (Snezhkina et al. 2020). In addition, the c.1A>G variant was identified in at least two individuals with an autosomal recessive mitochondrial disorder (Baskovich et al. 2016; Han et al. 2019; Yang et al. 2022). Different nucleotide changes that also disrupt the initiation codon, c.1A>C, c.1A>T, c.2T>C, c.2T>G, and c.3G>C, have been reported in individuals with adrenal paraganglioma, carotid paraganglioma, gastrointestinal stromal tumors, or autosomal recessive Leigh syndrome (Parfait et al. 2000; Jiang et al. 2015; Bausch et al. 2017; Carrera et al. 2019). The c.1A>G variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000044 in the European (non-Finnish) population (version 3.1.2). Mutagenesis studies using breast cancer cell lines expressing c.1A>G variant and wild-type cDNA showed decreased protein levels and increased accumulation of metabolites in the presence of the variant. The succinate to fumarate ratio was not significantly different from wild-type in the cell lines expressing the variant (Dubart Gault et al. 2018), but a sample from the resected pheochromocytoma from the individual with a germline c.1A>G variant did show an increased succinate to fumarate ratio as well as absent immunohistochemical staining for succinate dehydrogenase subunits A and B (Davidoff et al. 2021). Based on the available evidence, the c.1A>G (p.Met1?) variant is classified as likely pathogenic for hereditary paraganglioma-pheochromocytoma syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 2024	This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35014173, 28384794, 10746566, 26722403, 32971818]. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26334176, 30877234, 31665838, 29625052, 32971818, 32676327, 30068732, 33077847, Davidoff2021[Case Report]) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

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 affects the initiator methionine of the SDHA mRNA. The next in-frame methionine is located at codon 114. This variant is present in population databases (rs1061517, gnomAD 0.02%). Disruption of the initiator codon has been observed in individuals with autosomal dominant gastrointestinal stromal tumor syndrome, autosomal dominant paraganglioma-pheochromocytoma syndrome (PMID: 26722403, 28384794, 29625052, 30068732), and/or autosomal recessive mitochondrial complex II deficiency (PMID: 10746566, 26334176). ClinVar contains an entry for this variant (Variation ID: 239661). This variant disrupts the N-terminal part of the SDHA protein, which is important for FAD binding (PMID: 25488574, 15989954, 21858060). While functional studies have not been performed to directly test the effect of this variant on SDHA protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2022

The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the SDHA gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). There is an in-frame methionine 114 amino acids downstream from this initiation site which may result in an N-terminal truncation; however, direct evidence is unavailable. This alteration has been reported in at least one individual with Leigh syndrome (Baskovich B et al. Genet. Med. 2016 05;18:522-8). A different variant altering the methionine residue (c.1A>C) has been observed in an individual with Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans, as well as in individuals with paraganglioma and gastrointestinal stromal tumor (GIST) (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43; Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212; Carrera S et al. Hered. Cancer Clin. Pract. 2019 Aug;17:23). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.28

T;T;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Benign

-0.82

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Benign

-0.48

.;N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

.;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

0.0030, 0.012

.;B;B;.

Vest4

0.89

MVP

0.67

ClinPred

0.79

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.73

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