rs1057519567

chr7-76063553-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005918.4(MDH2):c.596del(p.Gly199AlafsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MDH2 NM_005918.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.06

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-76063553-TG-T is Pathogenic according to our data. Variant chr7-76063553-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 266121.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDH2	NM_005918.4	c.596del	p.Gly199AlafsTer10	frameshift_variant	6/9	ENST00000315758.10
MDH2	NM_001282403.2	c.470del	p.Gly157AlafsTer10	frameshift_variant	5/8
MDH2	NM_001282404.2	c.275del	p.Gly92AlafsTer10	frameshift_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDH2	ENST00000315758.10	c.596del	p.Gly199AlafsTer10	frameshift_variant	6/9	1	NM_005918.4	P1
MDH2	ENST00000432020.2	c.470del	p.Gly157AlafsTer10	frameshift_variant	5/8	2
MDH2	ENST00000443006.5	c.275del	p.Gly92AlafsTer10	frameshift_variant	5/8	2
MDH2	ENST00000424167.2	n.172del		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: criteria provided, single submitter

Submissions by phenotype

Infantile encephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Metabolic Diseases, Wilhelmina Children's Hospital

-

- -

Developmental and epileptic encephalopathy, 51 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057519567; hg19: chr7-75692871;