1-11965504-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000302.4(PLOD1):c.1495C>T(p.Arg499Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,613,106 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00043 ( 2 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.33

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]

PLOD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031227767).

BP6

Variant 1-11965504-C-T is Benign according to our data. Variant chr1-11965504-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 292304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000394 (60/152242) while in subpopulation EAS AF= 0.00598 (31/5180). AF 95% confidence interval is 0.00433. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4 link	c.1495C>T	p.Arg499Trp	missense_variant	Exon 14 of 19	ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_001316320.2 link	c.1636C>T	p.Arg546Trp	missense_variant	Exon 15 of 20		NP_001303249.1	Q02809-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLOD1	ENST00000196061.5 link	c.1495C>T	p.Arg499Trp	missense_variant	Exon 14 of 19	1	NM_000302.4	ENSP00000196061.4	Q02809-1
PLOD1	ENST00000470133.1 link	n.109C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3
PLOD1	ENST00000491536.5 link	n.123C>T		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00597

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000828

AC:

208

AN:

251170

Hom.:

AF XY:

0.000802

AC XY:

109

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00636

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000426

AC:

623

AN:

1460864

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

333

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00279

Gnomad4 EAS exome

AF:

0.00723

Gnomad4 SAS exome

AF:

0.00104

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000873

Gnomad4 OTH exome

AF:

0.000630

GnomAD4 genome

AF:

0.000394

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00598

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000445

Hom.:

Bravo

AF:

0.000404

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000873

AC:

106

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PLOD1: BS2 -

Jun 12, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Jan 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PLOD1 c.1495C>T (p.Arg499Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251170 control chromosomes, predominantly at a frequency of 0.0064 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4.048 fold of the estimated maximal expected allele frequency for a pathogenic variant in PLOD1 causing Ehlers-Danlos Syndrome Type VI phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1495C>T has been reported in the literature in individuals affected with TAD who also carried a pathogenic FBN1 variant (Gago-Diaz_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome Type VI. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

PLOD1-related disorder

Benign:1

Jul 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Oct 23, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.031

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.71

MVP

0.94

MPC

0.30

ClinPred

0.11

GERP RS

4.6

Varity_R

0.47

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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