1-11934783-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000302.4(PLOD1):c.4C>T(p.Arg2Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,385,284 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: 0.0000036 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.125

Publications

1 publications found

Variant links:

Genes affected

PLOD1 (HGNC:9081): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1) Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PLOD1 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, kyphoscoliotic type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

PLOD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
PLOD1	NM_000302.4 link	c.4C>T	p.Arg2Trp	missense_variant	Exon 1 of 19	ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_001316320.2 link	c.4C>T	p.Arg2Trp	missense_variant	Exon 1 of 20		NP_001303249.1	Q02809-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5 link	c.4C>T	p.Arg2Trp	missense_variant	Exon 1 of 19	1	NM_000302.4	ENSP00000196061.4		Q02809-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000378

AC:

AN:

132228

AF XY:

0.0000418

show subpopulations

Gnomad AFR exome

AF:

0.000169

Gnomad AMR exome

AF:

0.0000415

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000299

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1385284

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

683662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30796

American (AMR)

AF:

0.0000282

AC:

AN:

35512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25000

East Asian (EAS)

AF:

0.0000852

AC:

AN:

35226

South Asian (SAS)

AF:

0.00

AC:

AN:

78582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5016

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077296

Other (OTH)

AF:

0.00

AC:

AN:

57652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Feb 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R2W variant (also known as c.4C>T), located in coding exon 1 of the PLOD1 gene, results from a C to T substitution at nucleotide position 4. The arginine at codon 2 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Uncertain:1

Jun 02, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PLOD1 c.4C>T; p.Arg2Trp variant (rs1402614845), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found on only five chromosomes (5/132228 alleles) in the Genome Aggregation Database. The arginine at codon 2 is highly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Arg2Trp variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.0052

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

.;T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.45

T;T;T

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.7

.;.;L

PhyloP100

0.13

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.1

N;D;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.95

.;.;P

Vest4

0.22

MutPred

0.58

Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);

MVP

0.78

MPC

0.71

ClinPred

0.49

GERP RS

2.4

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.099

gMVP

0.59

Mutation Taster

=82/18

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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1-11934783-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over