2-206751064-C-A

Variant summary

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

The NM_001039845.3(MDH1B):​c.922G>T​(p.Val308Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,438,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18
Variant links:
Genes affected
MDH1B (HGNC:17836): (malate dehydrogenase 1B) Predicted to enable L-malate dehydrogenase activity. Predicted to be involved in NADH metabolic process; dicarboxylic acid metabolic process; and tricarboxylic acid cycle. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
MDH1BNM_001039845.3 linkc.922G>T p.Val308Leu missense_variant Exon 6 of 12 ENST00000374412.8 NP_001034934.1 Q5I0G3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MDH1BENST00000374412.8 linkc.922G>T p.Val308Leu missense_variant Exon 6 of 12 1 NM_001039845.3 ENSP00000363533.3 Q5I0G3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000278
AC:
4
AN:
1438420
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
715306
show subpopulations
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:
0.00000365
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.922G>T (p.V308L) alteration is located in exon 6 (coding exon 6) of the MDH1B gene. This alteration results from a G to T substitution at nucleotide position 922, causing the valine (V) at amino acid position 308 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.095
T;.;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
D;D;D
M_CAP
Benign
0.060
D
MetaRNN
Uncertain
0.53
D;D;D
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Uncertain
2.5
M;.;M
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.6
N;N;N
REVEL
Uncertain
0.35
Sift
Benign
0.21
T;T;T
Sift4G
Benign
0.24
T;T;T
Polyphen
0.25
B;.;B
Vest4
0.59
MutPred
0.46
Loss of MoRF binding (P = 0.1028);.;Loss of MoRF binding (P = 0.1028);
MVP
0.74
MPC
0.34
ClinPred
0.95
D
GERP RS
6.0
Varity_R
0.31
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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: chr2-207615788; COSMIC: COSV65590474; API