rs780770356

Positions:

• chr3-146071125-G-A
• chr3-146071125-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_182943.3(PLOD2):​c.2038C>T​(p.Arg680Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,458,924 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: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PLOD2 NM_182943.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.77

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.105 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-146071125-G-A is Pathogenic according to our data. Variant chr3-146071125-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-146071125-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD2	NM_182943.3	c.2038C>T	p.Arg680Ter	stop_gained	19/20	ENST00000282903.10
PLOD2	NM_000935.3	c.1975C>T	p.Arg659Ter	stop_gained	18/19
PLOD2	XM_017006625.3	c.1762C>T	p.Arg588Ter	stop_gained	20/21
PLOD2	XM_047448319.1	c.1762C>T	p.Arg588Ter	stop_gained	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD2	ENST00000282903.10	c.2038C>T	p.Arg680Ter	stop_gained	19/20	1	NM_182943.3	P3
	ENST00000480247.1	n.337+2947G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1458924 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 725812

Gnomad4 AFR exome AF: 0.0000300

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: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29177700, 33664768, 31472299, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 15, 2022	This sequence change creates a premature translational stop signal (p.Arg680*) in the PLOD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLOD2 are known to be pathogenic (PMID: 22689593, 25238597, 29178448). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bruck syndrome (PMID: 29177700). ClinVar contains an entry for this variant (Variation ID: 374012). For these reasons, this variant has been classified as Pathogenic. -

Bruck syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 08, 2019

- -

Clubfoot;C0345375:Short femur;C0432098:Cleft soft palate;C0685409:Camptodactyly;C1851310:Aplasia/hypoplasia of the femur;C1855340:Bowing of the long bones;C1859399:Radial bowing;C1859461:Femoral bowing;C1865847:Ulnar bowing Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	47
DANN	Uncertain	0.98
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.0045
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.88
GERP RS		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs780770356; hg19: chr3-145788912; COSMIC: COSV51469342; COSMIC: COSV51469342;