rs118204021

Positions:

• chr14-50302994-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_024884.3(L2HGDH):​c.164G>A​(p.Gly55Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.29

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_024884.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 14-50302994-C-T is Pathogenic according to our data. Variant chr14-50302994-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1610.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-50302994-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-50302994-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L2HGDH	NM_024884.3	c.164G>A	p.Gly55Asp	missense_variant	2/10	ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.164G>A	p.Gly55Asp	missense_variant	2/10	1	NM_024884.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459814 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726428

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

L-2-hydroxyglutaric aciduria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2004

- -

L2HGDH-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

The L2HGDH c.164G>A variant is predicted to result in the amino acid substitution p.Gly55Asp. This variant was reported in the homozygous state in four individuals from three families; all individuals had biochemically confirmed L-2-Hydroxyglutaric aciduria (Topcu et al. 2004. PubMed ID: 15385440). It was also reported in the compound heterozygous state with a pathogenic frameshift variant in two affected relatives (Sass et al. 2008. PubMed ID: 18415700). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.3	.;H;H;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.95
MutPred		0.79		Gain of catalytic residue at G55 (P = 0);Gain of catalytic residue at G55 (P = 0);Gain of catalytic residue at G55 (P = 0);Gain of catalytic residue at G55 (P = 0);Gain of catalytic residue at G55 (P = 0);
MVP		0.99
MPC		0.92
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs118204021; hg19: chr14-50769712;