5-236519-G-C

Variant names:

• chr5-236519-G-C
• rs370690436
• NM_004168.4:c.1352G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_004168.4(SDHA):​c.1352G>C​(p.Arg451Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R451S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.58
• 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: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 34 uncertain in NM_004168.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-236518-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 969346.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

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.1352G>C	p.Arg451Pro	missense	Exon 10 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.1208G>C	p.Arg403Pro	missense	Exon 9 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.1352G>C	p.Arg451Pro	missense	Exon 10 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.1352G>C	p.Arg451Pro	missense	Exon 10 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.*85G>C		non_coding_transcript_exon	Exon 9 of 24	ENSP00000499215.1	A0A494C1T6
	ENSG00000286001	ENST00000651543.1		n.*85G>C		3_prime_UTR	Exon 9 of 24	ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	5.3	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.90		Loss of methylation at R451 (P = 0.018)
MVP		0.88
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		0.025	Neutral
Varity_R		0.98
gMVP		0.99
Mutation Taster		=6/94	disease causing

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: rs370690436; hg19: chr5-236634; COSMIC: COSV99371304; COSMIC: COSV99371304;