14-50247179-C-G

Variant names:

• chr14-50247179-C-G
• rs1888055214
• NM_024884.3:c.1271G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024884.3(L2HGDH):​c.1271G>C​(p.Gly424Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G424E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

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.1271G>C	p.Gly424Ala	missense	Exon 10 of 10	NP_079160.1	Q9H9P8-1
	L2HGDH	NM_001425212.1		c.1271G>C	p.Gly424Ala	missense	Exon 10 of 11	NP_001412141.1	Q9H9P8-1
	L2HGDH	NM_001425213.1		c.1160G>C	p.Gly387Ala	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.1271G>C	p.Gly424Ala	missense	Exon 10 of 10	ENSP00000267436.4	Q9H9P8-1
	L2HGDH	ENST00000261699.8	TSL:1	c.1197-9454G>C		intron	N/A	ENSP00000261699.4	C9JVN9
	L2HGDH	ENST00000889799.1		c.1394G>C	p.Gly465Ala	missense	Exon 11 of 11	ENSP00000559858.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.88
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.72
MutPred		0.59		Gain of catalytic residue at D422 (P = 2e-04)
MVP		0.90
MPC		0.83
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.60
gMVP		0.83
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs1888055214; hg19: chr14-50713897;