chr5-218356-A-G

Variant names:

• chr5-218356-A-G
• rs1061517
• NM_004168.4:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.636
• Publications: 28 publications found

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]

ENSG00000286001 (HGNC:):

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 61 pathogenic variants. Next in-frame start position is after 114 codons. Genomic position: 225446. Lost 0.170 part of the original CDS.
• PS1: Another start lost variant in NM_004168.4 (SDHA) was described as [Pathogenic] in ClinVar as 3602705
• 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 rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENST00000264932.11	NP_004159.2
CCDC127	NM_145265.3	c.-274T>C		upstream_gene_variant		ENST00000296824.4	NP_660308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1A>G	p.Met1?	start_lost	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1
CCDC127	ENST00000296824.4	c.-274T>C		upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 34

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

GnomAD2 exomes AF: 0.00000871 AC: 1 AN: 114846 AF XY: 0.0000151

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000172

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000214 AC: 28 AN: 1308140 Hom.: 0 Cov.: 31 AF XY: 0.0000232 AC XY: 15 AN XY: 645810

African (AFR) AF: 0.00 AC: 0 AN: 26884

American (AMR) AF: 0.00 AC: 0 AN: 25114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20462

East Asian (EAS) AF: 0.0000322 AC: 1 AN: 31060

South Asian (SAS) AF: 0.00 AC: 0 AN: 66254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3694

European-Non Finnish (NFE) AF: 0.0000239 AC: 25 AN: 1047198

Other (OTH) AF: 0.0000374 AC: 2 AN: 53516

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5196

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000136 AC: 1

ExAC AF: 0.0000177 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 5 Pathogenic:4

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SDHA-related disorders (MIM#613642, MIM#252011, MIM#619259, MIM#614165) . (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene are known to have reduced penetrance for paragangliomas 5 (PMID: 29978154). (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 and v3: 16 heterozygotes, 0 homozygotes). (SP) 0311 - Multiple alternative nucleotide changes at the same initiation codon have been observed in gnomAD (v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0701 - Other canonical translation initiation codon variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Seven variants affecting the canonical translation initiation codon have been observed in heterozygous or compound heterozygous states in multiple individuals with paragangliomas 5 (MIM#614165) and mitochondrial respiratory chain complex II deficiency (MIM#252011) respectively (ClinVar, PMIDs: 10746566, 26722403, 31413764). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in association with paragangliomas. In addition, it has also been reported in a compound heterozygous state in an individual with Leigh syndrome (ClinVar, PMID: 35014173). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 06, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Jun 15, 2022

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 06, 2018

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2

Jan 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 24, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	16
DANN	Benign	0.46
DEOGEN2	Benign	0.28	T;T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.82	T
PhyloP100		0.64
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	D
GERP RS		2.5
PromoterAI		-0.46	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.73
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1061517; hg19: chr5-218471; COSMIC: COSV53766805; COSMIC: COSV53766805;