rs1057519566

Positions:

• chr7-76063579-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000315758.10(MDH2):​c.620C>T​(p.Pro207Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MDH2 ENST00000315758.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.09

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 7-76063579-C-T is Pathogenic according to our data. Variant chr7-76063579-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265770.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDH2	NM_005918.4	c.620C>T	p.Pro207Leu	missense_variant	6/9	ENST00000315758.10	NP_005909.2
MDH2	NM_001282403.2	c.494C>T	p.Pro165Leu	missense_variant	5/8		NP_001269332.1
MDH2	NM_001282404.2	c.299C>T	p.Pro100Leu	missense_variant	5/8		NP_001269333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDH2	ENST00000315758.10	c.620C>T	p.Pro207Leu	missense_variant	6/9	1	NM_005918.4	ENSP00000327070	P1
MDH2	ENST00000432020.2	c.494C>T	p.Pro165Leu	missense_variant	5/8	2		ENSP00000408649
MDH2	ENST00000443006.5	c.299C>T	p.Pro100Leu	missense_variant	5/8	2		ENSP00000416929
MDH2	ENST00000424167.2	n.196C>T		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Infantile encephalopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice-Université Côte d'Azur

-

- -

Developmental and epileptic encephalopathy, 51 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	4.5	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-9.3	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.88		Gain of sheet (P = 0.0344);.;.;
MVP		0.93
MPC		0.72
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519566; hg19: chr7-75692897;