14-50283990-T-G

Variant names:

• chr14-50283990-T-G
• NM_024884.3:c.584A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_024884.3(L2HGDH):​c.584A>C​(p.Tyr195Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. Y195C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.31

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50283990-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L2HGDH	NM_024884.3	c.584A>C	p.Tyr195Ser	missense_variant	Exon 5 of 10	ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9	c.584A>C	p.Tyr195Ser	missense_variant	Exon 5 of 10	1	NM_024884.3	ENSP00000267436.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.2	.;L;L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.79
MutPred		0.66		Gain of catalytic residue at T190 (P = 0);Gain of catalytic residue at T190 (P = 0);Gain of catalytic residue at T190 (P = 0);Gain of catalytic residue at T190 (P = 0);
MVP		0.86
MPC		0.94
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr14-50750708;