5-256376-G-C

Variant names:

• chr5-256376-G-C
• rs375396913
• NM_004168.4:c.1951G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004168.4(SDHA):​c.1951G>C​(p.Glu651Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E651D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.40
• Publications: 7 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: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

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

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

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

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33525816).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.1951G>C	p.Glu651Gln	missense	Exon 15 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.1807G>C	p.Glu603Gln	missense	Exon 14 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.1708G>C	p.Glu570Gln	missense	Exon 13 of 13	NP_001317687.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.1951G>C	p.Glu651Gln	missense	Exon 15 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.*684G>C		non_coding_transcript_exon	Exon 14 of 24	ENSP00000499215.1
	ENSG00000286001	ENST00000651543.1		n.*684G>C		3_prime_UTR	Exon 14 of 24	ENSP00000499215.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251182 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461592 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111776

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Pheochromocytoma/paraganglioma syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.086
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.34
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.10	B
Vest4		0.47
MutPred		0.48		Loss of ubiquitination at K647 (P = 0.0787)
MVP		0.71
MPC		0.54
ClinPred		0.66	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.35
gMVP		0.71
Mutation Taster		=82/18	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

Other links and lift over

dbSNP: rs375396913; hg19: chr5-256491;