chr7-101206341-G-T

Position:

• chr7-101206341-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001084.5(PLOD3):​c.2157C>A​(p.His719Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLOD3 NM_001084.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00200

Genes affected

PLOD3 (HGNC:9083): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 3) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity PLOD3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD3	NM_001084.5	c.2157C>A	p.His719Gln	missense_variant	19/19	ENST00000223127.8	NP_001075.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD3	ENST00000223127.8	c.2157C>A	p.His719Gln	missense_variant	19/19	1	NM_001084.5	ENSP00000223127.3
PLOD3	ENST00000454310.5	c.732C>A	p.His244Gln	missense_variant	7/7	5		ENSP00000407555.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2023

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 expected to disrupt PLOD3 protein function. 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. This variant has not been reported in the literature in individuals affected with PLOD3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 719 of the PLOD3 protein (p.His719Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	0.042
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.91		Gain of catalytic residue at H719 (P = 0.0487);
MVP		0.95
MPC		0.61
ClinPred		1.0	D
GERP RS		-2.9
Varity_R		0.98
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-100849622; COSMIC: COSV56185314; COSMIC: COSV56185314;