14-50283988-G-C

Variant names:

• chr14-50283988-G-C
• rs368140834
• NM_024884.3:c.586C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024884.3(L2HGDH):​c.586C>G​(p.Arg196Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign 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. R196W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• Publications: 3 publications found

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]

L2HGDH Gene-Disease associations (from GenCC):

• L-2-hydroxyglutaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024884.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	NM_024884.3	MANE Select	c.586C>G	p.Arg196Gly	missense	Exon 5 of 10	NP_079160.1
	L2HGDH	NM_001425212.1		c.586C>G	p.Arg196Gly	missense	Exon 5 of 11	NP_001412141.1
	L2HGDH	NM_001425213.1		c.475C>G	p.Arg159Gly	missense	Exon 6 of 12	NP_001412142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.586C>G	p.Arg196Gly	missense	Exon 5 of 10	ENSP00000267436.4
	L2HGDH	ENST00000261699.8	TSL:1	c.586C>G	p.Arg196Gly	missense	Exon 5 of 10	ENSP00000261699.4
	L2HGDH	ENST00000555423.5	TSL:1	c.586C>G	p.Arg196Gly	missense	Exon 5 of 6	ENSP00000450494.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.95	L
PhyloP100		3.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.27
Sift	Benign	0.54	T
Sift4G	Benign	0.49	T
Polyphen		0.0030	B
Vest4		0.65
MutPred		0.65		Gain of catalytic residue at D194 (P = 2e-04)
MVP		0.72
MPC		0.27
ClinPred		0.78	D
GERP RS		4.6
Varity_R		0.18
gMVP		0.73
Mutation Taster		=82/18	polymorphism

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: rs368140834; hg19: chr14-50750706;