5-233578-G-T

Variant names:

• chr5-233578-G-T
• rs1062468
• NM_004168.4:c.997G>T
• SDHA p.Val333Phe

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004168.4(SDHA):​c.997G>T​(p.Val333Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V333I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.89
• Publications: 0 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]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Illumina, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.997G>T	p.Val333Phe	missense	Exon 8 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.853G>T	p.Val285Phe	missense	Exon 7 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.997G>T	p.Val333Phe	missense	Exon 8 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.997G>T	p.Val333Phe	missense	Exon 8 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.997G>T		non_coding_transcript_exon	Exon 8 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.997G>T	p.Val333Phe	missense	Exon 8 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Varity_R		0.34
gMVP		0.78
Mutation Taster		=72/28	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1062468;

hg19: chr5-233693;