rs1057519567

Variant names:

• chr7-76063553-TG-T
• rs1057519567
• NM_005918.4:c.596delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005918.4(MDH2):​c.596delG​(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
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 266121.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005918.4. 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
	MDH2	NM_005918.4	MANE Select	c.596delG	p.Gly199AlafsTer10	frameshift	Exon 6 of 9	NP_005909.2
	MDH2	NM_001282403.2		c.470delG	p.Gly157AlafsTer10	frameshift	Exon 5 of 8	NP_001269332.1	P40926-2
	MDH2	NM_001282404.2		c.275delG	p.Gly92AlafsTer10	frameshift	Exon 5 of 8	NP_001269333.1	G3XAL0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH2	ENST00000315758.10	TSL:1 MANE Select	c.596delG	p.Gly199AlafsTer10	frameshift	Exon 6 of 9	ENSP00000327070.5	P40926-1
	MDH2	ENST00000971443.1		c.596delG	p.Gly199AlafsTer10	frameshift	Exon 6 of 9	ENSP00000641502.1
	MDH2	ENST00000854579.1		c.596delG	p.Gly199AlafsTer10	frameshift	Exon 6 of 9	ENSP00000524638.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 51 (1)
1	-	-	Infantile encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519567; hg19: chr7-75692871;