rs121913551

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000302.4(PLOD1):​c.2032G>A​(p.Gly678Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G678G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000012 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PLOD1
NM_000302.4 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 10.0
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 1-11974656-G-A is Pathogenic according to our data. Variant chr1-11974656-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11974656-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLOD1NM_000302.4 linkc.2032G>A p.Gly678Arg missense_variant 19/19 ENST00000196061.5 NP_000293.2 Q02809-1
PLOD1NM_001316320.2 linkc.2173G>A p.Gly725Arg missense_variant 20/20 NP_001303249.1 Q02809-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLOD1ENST00000196061.5 linkc.2032G>A p.Gly678Arg missense_variant 19/191 NM_000302.4 ENSP00000196061.4 Q02809-1
PLOD1ENST00000481933.1 linkn.1459G>A non_coding_transcript_exon_variant 2/22
PLOD1ENST00000491536.5 linkn.384-627G>A intron_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152134
Hom.:
0
Cov.:
31
FAILED QC
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000281
AC:
7
AN:
249282
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135072
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1460908
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
726732
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
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:
0.00000810
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152134
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74322
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Pathogenic:5
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinSep 27, 2022ACMG classification criteria: PS4 moderated, PM2 supporting, PM3 strong, PP3 supporting -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 678 of the PLOD1 protein (p.Gly678Arg). This variant is present in population databases (rs121913551, gnomAD 0.02%). This missense change has been observed in individual(s) with Ehlers Danlos syndrome type VI (PMID: 8163671, 21699693). ClinVar contains an entry for this variant (Variation ID: 14366). 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 PLOD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PLOD1 function (PMID: 25637337). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 1994- -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 26, 2024- -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
36
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.2
H
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.1
D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.92
MVP
0.97
MPC
0.87
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.89
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.89
Position offset: 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.

Other links and lift over

dbSNP: rs121913551; hg19: chr1-12034713; COSMIC: COSV52151092; API