5-251101-G-T

Variant names:

• chr5-251101-G-T
• rs376391115
• NM_004168.4:c.1661G>T

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.1661G>T​(p.Arg554Leu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R554Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHA NM_004168.4 missense, splice_region
• Scores: Splicing: ADA: 0.01597
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.09
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 33 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 chr5-251100-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 8742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

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.1661G>T	p.Arg554Leu	missense splice_region	Exon 12 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.1517G>T	p.Arg506Leu	missense splice_region	Exon 11 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.1552-3292G>T		intron	N/A	NP_001317687.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.1661G>T	p.Arg554Leu	missense splice_region	Exon 12 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.*394G>T		splice_region non_coding_transcript_exon	Exon 11 of 24	ENSP00000499215.1
	ENSG00000286001	ENST00000651543.1		n.*394G>T		3_prime_UTR	Exon 11 of 24	ENSP00000499215.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.047	B
Vest4		0.90
MutPred		0.83		Loss of MoRF binding (P = 0.0386)
MVP		0.86
MPC		0.65
ClinPred		0.99	D
GERP RS		3.6
PromoterAI		0.0094	Neutral
Varity_R		0.77
gMVP		0.84
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.27
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: rs376391115; hg19: chr5-251216;