14-50247071-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024884.3(L2HGDH):c.1379G>T(p.Arg460Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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:1
• Conservation: PhyloP100: 5.81

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L2HGDH	NM_024884.3	c.1379G>T	p.Arg460Ile	missense_variant	10/10	ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.1379G>T	p.Arg460Ile	missense_variant	10/10	1	NM_024884.3	P1
L2HGDH	ENST00000261699.8	c.1197-9346G>T		intron_variant		1
L2HGDH	ENST00000421284.7	c.1379G>T	p.Arg460Ile	missense_variant	10/11	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

L-2-hydroxyglutaric aciduria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1998377). This variant has not been reported in the literature in individuals affected with L2HGDH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 460 of the L2HGDH protein (p.Arg460Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.0024
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.42
Sift	Benign	0.041	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.18	B;B
Vest4		0.71
MutPred		0.43		Loss of disorder (P = 0.0406);Loss of disorder (P = 0.0406);
MVP		0.76
MPC		0.92
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.45
gMVP		0.84

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50713789;