NM_001084.5(PLOD3):c.670G>C (p.Gly224Arg) AND Bone fragility with contractures, arterial rupture, and deafness

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 30, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002225136.2

Allele description [Variation Report for NM_001084.5(PLOD3):c.670G>C (p.Gly224Arg)]

NM_001084.5(PLOD3):c.670G>C (p.Gly224Arg)

Gene:

PLOD3:procollagen-lysine,2-oxoglutarate 5-dioxygenase 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q22.1

Genomic location:

Preferred name:

NM_001084.5(PLOD3):c.670G>C (p.Gly224Arg)

HGVS:

NC_000007.14:g.101215098C>G
NG_012148.1:g.7633G>C
NM_001084.5:c.670G>CMANE SELECT
NP_001075.1:p.Gly224Arg
NC_000007.13:g.100858379C>G
NM_001084.4:c.670G>C

Protein change:

G224R

Links:

dbSNP: rs377578690

NCBI 1000 Genomes Browser:

rs377578690

Molecular consequence:

NM_001084.5:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Bone fragility with contractures, arterial rupture, and deafness
Synonyms:: LH3 DEFICIENCY; LYSYL HYDROXYLASE 3 DEFICIENCY; BCARD SYNDROME; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012892; MedGen: C2676285; OMIM: 612394

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002503733	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 30, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18834968, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002503733

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 30, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.

Salo AM, Cox H, Farndon P, Moss C, Grindulis H, Risteli M, Robins SP, Myllylä R.

Am J Hum Genet. 2008 Oct;83(4):495-503. doi: 10.1016/j.ajhg.2008.09.004. Epub 2008 Oct 2.

PubMed [citation]

PMID:: 18834968
PMCID:: PMC2561927

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002503733.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change is predicted to replace glycine with arginine at codon 224 of the PLOD3 protein (p.(Gly224Arg)). The glycine residue is highly conserved but arginine is present in a single higher vertebrate (100 vertebrates, UCSC), and is located in a region required for glycosyltransferase activity (UniProt). There is a large physicochemical difference between glycine and arginine. The variant is present in a large population cohort at a frequency of 0.009%, which is consistent with a recessive condition (rs377578690, 26/282,890 alleles, 0 homozygotes in gnomAD v2.1). The variant has not bee reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). A missense variant affecting an adjacent amino acid (p.Asn223Ser) has been identified in an individual with lysyl hydroxylase 3 deficiency (PMID: 18834968). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as a VARIANT OF UUNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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