5-218357-T-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_004168.4(SDHA):c.2T>A(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 0.00000153 in 1,309,370 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SDHA NM_004168.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.08

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-218357-T-A is Pathogenic according to our data. Variant chr5-218357-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 582115.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	c.2T>A	p.Met1?	start_lost	1/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11	c.2T>A	p.Met1?	start_lost	1/15	1	NM_004168.4	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000866 AC: 1 AN: 115518 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000624

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1309370 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 646500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000393

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.54e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ExAC AF: 0.00000887 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

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 (rs750380279, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with gastrointestinal stromal tumor, renal cell carcinoma, paraganglioma, pheochromocytoma, and complex II deficiency (PMID: 10746566, 26334176, 26722403, 28384794). ClinVar contains an entry for this variant (Variation ID: 582115). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SDHA function (PMID: 10746566). Rescue of translational initiation by the downstream methionine would be expected to result in the disruption of the N-terminal part of the SDHA protein, which is important for FAD binding (PMID: 25488574, 15989954). 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

Nov 16, 2020

The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the SDHA gene and results from a T to A substitution at nucleotide position 2. 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. Other alterations impacting the initiation codon (c.2T>C, c.2T>G, c.1A>C, c.1A>G) have been reported in individuals with personal history consistent with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, including gastrointestinal stromal tumor (GIST), renal cell carcinoma, and carotid paraganglioma (Jiang Q et al. Int J Clin Exp Pathol 2015 Oct;8(10):12188-97; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Carrera S et al. Hered. Cancer Clin. Pract. 2019 Aug;17:23). Further, the c.1A>C alteration impacting the SDHA initiation codon has been observed in an individual with autosomal recessive Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43). 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. -

Paragangliomas 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 12, 2023

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]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	21
Dann	Benign	0.88
DEOGEN2	Benign	0.29	T;T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.32, 0.21	.;B;B;.
Vest4		0.84
MutPred		0.96		Gain of catalytic residue at M1 (P = 0.0061);Gain of catalytic residue at M1 (P = 0.0061);Gain of catalytic residue at M1 (P = 0.0061);Gain of catalytic residue at M1 (P = 0.0061);
MVP		0.78
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.87

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

Other links and lift over

dbSNP: rs750380279; hg19: chr5-218472;