rs121434461

Positions:

chr3-146071416-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_182943.3(PLOD2):c.1856G>A(p.Arg619His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,022 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 Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PLOD2
NM_182943.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

PLOD2 (HGNC:9082): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) The protein encoded by this gene is a membrane-bound homodimeric enzyme that is localized to the cisternae of the rough 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 VIB have deficiencies in lysyl hydroxylase activity. Mutations in the coding region of this gene are associated with Bruck syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

PLOD2 links:

PLOD2 (HGNC:):

PLOD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 3-146071416-C-T is Pathogenic according to our data. Variant chr3-146071416-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7643.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-146071416-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD2	NM_182943.3 linkuse as main transcript	c.1856G>A	p.Arg619His	missense_variant	18/20	ENST00000282903.10	NP_891988.1	O00469-2
PLOD2	NM_000935.3 linkuse as main transcript	c.1793G>A	p.Arg598His	missense_variant	17/19		NP_000926.2	O00469-1
PLOD2	XM_017006625.3 linkuse as main transcript	c.1580G>A	p.Arg527His	missense_variant	19/21		XP_016862114.1
PLOD2	XM_047448319.1 linkuse as main transcript	c.1580G>A	p.Arg527His	missense_variant	18/20		XP_047304275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD2	ENST00000282903.10 linkuse as main transcript	c.1856G>A	p.Arg619His	missense_variant	18/20	1	NM_182943.3	ENSP00000282903.5		O00469-2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151630

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250544

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1459392

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000811

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151630

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74044

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bruck syndrome 2

Pathogenic:2Uncertain:1

Uncertain significance, no assertion criteria provided	research	Department of Traditional Chinese Medicine, Fujian Provincial Hospital	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The missense c.1856G>A p.Arg619His variant in PLOD2 gene has been reported previously in homozygous state in multiple individuals affected with Bruck syndrome Ha-Vinh et al., 2004; Puig-Hervás et al., 2012; Caparros-Martin et al., 2016; Mumm et al., 2020; Wang et al., 2022. This variant has also been previously identified in homozygous state in proband and heterozygous state in parents and sisters Ha-Vinh et al., 2004; Wang et al., 2022. The p.Arg619His variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Pathogenic. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position in PLOD2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. TThe amino acid Arg at position 619 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

.;.;D;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.3

.;.;M;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0, 1.0

.;D;D;D

Vest4

0.83

MutPred

0.80

.;.;Gain of glycosylation at Y603 (P = 0.0155);.;

MVP

0.93

MPC

0.45

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over