14-50247108-C-T

Variant names:

• chr14-50247108-C-T
• rs868287441
• NM_024884.3:c.1342G>A

Variant summary

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

The NM_024884.3(L2HGDH):​c.1342G>A​(p.Ala448Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A448P) 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: 3.20
• Publications: 0 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: G2P, Ambry Genetics, 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	NM_024884.3	MANE Select	c.1342G>A	p.Ala448Thr	missense	Exon 10 of 10	NP_079160.1	Q9H9P8-1
	L2HGDH	NM_001425212.1		c.1342G>A	p.Ala448Thr	missense	Exon 10 of 11	NP_001412141.1	Q9H9P8-1
	L2HGDH	NM_001425213.1		c.1231G>A	p.Ala411Thr	missense	Exon 11 of 12	NP_001412142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.1342G>A	p.Ala448Thr	missense	Exon 10 of 10	ENSP00000267436.4	Q9H9P8-1
	L2HGDH	ENST00000261699.8	TSL:1	c.1197-9383G>A		intron	N/A	ENSP00000261699.4	C9JVN9
	L2HGDH	ENST00000889799.1		c.1465G>A	p.Ala489Thr	missense	Exon 11 of 11	ENSP00000559858.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D
Eigen	Benign	0.13
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.15	B
Vest4		0.36
MutPred		0.70		Gain of catalytic residue at I453 (P = 0.0069)
MVP		0.81
MPC		0.31
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.67
gMVP		0.89
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs868287441; hg19: chr14-50713826;