7-76058047-C-A

Variant names:

• chr7-76058047-C-A
• rs375002796
• NM_005918.4:c.398C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_005918.4(MDH2):​c.398C>A​(p.Pro133Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P133L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDH2 NM_005918.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.32
• Publications: 0 publications found

Genes affected

MDH2 (HGNC:6971): (malate dehydrogenase 2) Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

MDH2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 51

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-76058047-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 265769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDH2	NM_005918.4	c.398C>A	p.Pro133Gln	missense_variant	Exon 4 of 9	ENST00000315758.10	NP_005909.2
MDH2	NM_001282403.2	c.398C>A	p.Pro133Gln	missense_variant	Exon 4 of 8		NP_001269332.1
MDH2	NM_001282404.2	c.77C>A	p.Pro26Gln	missense_variant	Exon 3 of 8		NP_001269333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH2	ENST00000315758.10	c.398C>A	p.Pro133Gln	missense_variant	Exon 4 of 9	1	NM_005918.4	ENSP00000327070.5
MDH2	ENST00000432020.2	c.398C>A	p.Pro133Gln	missense_variant	Exon 4 of 8	2		ENSP00000408649.2
MDH2	ENST00000443006.5	c.77C>A	p.Pro26Gln	missense_variant	Exon 3 of 8	2		ENSP00000416929.1
MDH2	ENST00000461665.5	n.423C>A		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;H
PhyloP100		7.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.4	D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.86
MutPred		0.80		Gain of catalytic residue at P133 (P = 0.1709);.;Gain of catalytic residue at P133 (P = 0.1709);
MVP		0.98
MPC		0.69
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.84
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: rs375002796; hg19: chr7-75687365;