Genetic Variant NM_017448.5:c.505C>A (chr11-18434826-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_017448.5(LDHC):c.505C>A(p.Arg169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,126 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. R169C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LDHC
NM_017448.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

Publications

0 publications found

Variant links:

Genes affected

LDHC (HGNC:6544): (lactate dehydrogenase C) Lactate dehydrogenase C catalyzes the conversion of L-lactate and NAD to pyruvate and NADH in the final step of anaerobic glycolysis. LDHC is testis-specific and belongs to the lactate dehydrogenase family. Two transcript variants have been detected which differ in the 5' untranslated region. [provided by RefSeq, Jul 2008]

LDHC links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity LDHC_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDHC	NM_017448.5 link	c.505C>A	p.Arg169Ser	missense_variant	Exon 5 of 8	ENST00000541669.6	NP_059144.1	P07864A0A140VKA7
LDHC	NM_002301.5 link	c.505C>A	p.Arg169Ser	missense_variant	Exon 5 of 8		NP_002292.1	P07864A0A140VKA7
LDHC	XM_047426934.1 link	c.157C>A	p.Arg53Ser	missense_variant	Exon 3 of 6		XP_047282890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDHC	ENST00000541669.6 link	c.505C>A	p.Arg169Ser	missense_variant	Exon 5 of 8	1	NM_017448.5	ENSP00000437783.1		P07864

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459126

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726086

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109542

Other (OTH)

AF:

0.00

AC:

AN:

60278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;D;.;D;D;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.71

.;T;T;T;T;T

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;H;.;.;.;.

PhyloP100

1.6

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.1

D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

0.97

MutPred

0.91

Loss of methylation at R169 (P = 0.0257);Loss of methylation at R169 (P = 0.0257);.;.;Loss of methylation at R169 (P = 0.0257);Loss of methylation at R169 (P = 0.0257);

MVP

0.99

MPC

0.55

ClinPred

1.0

GERP RS

4.7

Varity_R

0.97

gMVP

0.90

Mutation Taster

=10/90

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over