dbSNP rs373172891: L2HGDH:p.Ile392Val (chr14-50265380-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024884.3(L2HGDH):c.1174A>G(p.Ile392Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,611,802 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I392T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 6 hom. )

Consequence

L2HGDH
NM_024884.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.14

Publications

3 publications found

Variant links:

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

L2HGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011918634).

BP6

Variant 14-50265380-T-C is Benign according to our data. Variant chr14-50265380-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435698.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000164 (25/152298) while in subpopulation EAS AF = 0.00482 (25/5184). AF 95% confidence interval is 0.00335. There are 1 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
L2HGDH	NM_024884.3	MANE Select	c.1174A>G	p.Ile392Val	missense	Exon 9 of 10	NP_079160.1	Q9H9P8-1
L2HGDH	NM_001425212.1		c.1174A>G	p.Ile392Val	missense	Exon 9 of 11	NP_001412141.1	Q9H9P8-1
L2HGDH	NM_001425213.1		c.1063A>G	p.Ile355Val	missense	Exon 10 of 12	NP_001412142.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.1174A>G	p.Ile392Val	missense	Exon 9 of 10	ENSP00000267436.4	Q9H9P8-1
L2HGDH	ENST00000261699.8	TSL:1	c.1174A>G	p.Ile392Val	missense	Exon 9 of 10	ENSP00000261699.4	C9JVN9
L2HGDH	ENST00000889799.1		c.1297A>G	p.Ile433Val	missense	Exon 10 of 11	ENSP00000559858.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00481

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000279

AC:

AN:

251252

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000210

AC:

306

AN:

1459504

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

150

AN XY:

726272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00749

AC:

297

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109964

Other (OTH)

AF:

0.0000995

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00482

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

L-2-hydroxyglutaric aciduria (1)

L2HGDH-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.099

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.0080

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.33

PhyloP100

2.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.64

REVEL

Benign

0.22

Sift

Benign

0.44

Sift4G

Benign

0.61

Polyphen

0.22

Vest4

0.13

MutPred

0.64

Gain of catalytic residue at D396 (P = 0.057)

MVP

0.58

MPC

0.19

ClinPred

0.078

GERP RS

5.2

Varity_R

0.038

gMVP

0.40

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over