11-18396925-T-C

Position:

• chr11-18396925-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005566.4(LDHA):​c.83T>C​(p.Val28Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,794 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LDHA NM_005566.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

Genes affected

LDHA (HGNC:6535): (lactate dehydrogenase A) This gene encodes the A subunit of lactate dehydrogenase enzyme which catalyzes the reversible conversion of pyruvate to lactate with the concomitant oxidation of NADH to NAD in anaerobic glycolysis. The protein is found predominantly in skeletal muscle and belongs to the lactate dehydrogenase family. Mutations in this gene have been linked to exertional myoglobinuria. The human genome contains several non-transcribed pseudogenes of this gene. [provided by RefSeq, Sep 2023]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDHA	NM_005566.4	c.83T>C	p.Val28Ala	missense_variant	2/8	ENST00000422447.8	NP_005557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDHA	ENST00000422447.8	c.83T>C	p.Val28Ala	missense_variant	2/8	1	NM_005566.4	ENSP00000395337	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251450 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461794 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727194

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 28 of the LDHA protein (p.Val28Ala). This variant is present in population databases (rs776016684, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 2097402). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LDHA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;D;.;.;.;.;D;D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	.;T;T;T;T;T;T;T;T;.;T;T
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	-0.030	N;.;N;N;.;N;.;.;.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N;D;N;D;D;N;D;D;N;N;N;.
REVEL	Pathogenic	0.75
Sift	Benign	0.062	T;D;D;D;D;D;D;D;T;T;T;.
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.046	B;.;.;.;.;.;.;.;.;B;B;.
Vest4		0.89
MutPred		0.57		Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);.;Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);Loss of stability (P = 0.1318);
MVP		0.96
MPC		0.72
ClinPred		0.88	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs776016684; hg19: chr11-18418472;