14-50247237-T-C

Position:

• chr14-50247237-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024884.3(L2HGDH):​c.1213A>G​(p.Arg405Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.484

Genes affected

L2HGDH (HGNC:20499): (L-2-hydroxyglutarate dehydrogenase) This gene encodes L-2-hydroxyglutarate dehydrogenase, a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe cognitive disability. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L2HGDH	NM_024884.3	c.1213A>G	p.Arg405Gly	missense_variant	10/10	ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9	c.1213A>G	p.Arg405Gly	missense_variant	10/10	1	NM_024884.3	ENSP00000267436	P1
L2HGDH	ENST00000261699.8	c.1197-9512A>G		intron_variant		1		ENSP00000261699
L2HGDH	ENST00000421284.7	c.1213A>G	p.Arg405Gly	missense_variant	10/11	2		ENSP00000405559	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

L-2-hydroxyglutaric aciduria Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	-	- -
Uncertain significance, criteria provided, single submitter	research	Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences	Jul 05, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.82		Gain of catalytic residue at A402 (P = 0);Gain of catalytic residue at A402 (P = 0);
MVP		0.76
MPC		0.91
ClinPred		1.0	D
GERP RS		-4.5
Varity_R		0.97
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: rs1888059303; hg19: chr14-50713955;