rs1032781250

chr1-11960765-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000302.4(PLOD1):c.1095C>T(p.Gly365=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9990

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 1.97

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-11960765-C-T is Pathogenic according to our data. Variant chr1-11960765-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 580535.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4 linkuse as main transcript	c.1095C>T	p.Gly365=	splice_region_variant, synonymous_variant	10/19	ENST00000196061.5
PLOD1	NM_001316320.2 linkuse as main transcript	c.1236C>T	p.Gly412=	splice_region_variant, synonymous_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5 linkuse as main transcript	c.1095C>T	p.Gly365=	splice_region_variant, synonymous_variant	10/19	1	NM_000302.4	P1	Q02809-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460644

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 27, 2022	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP3 supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The splice region variant c.1095C>T(p.Gly365) variant has been reported in homozygous state in patients affected with Ehlers-Danlos syndrome (Rohrbach M, et. al., 2011; Yan X, et. al., 2022). The variant is reported with an allele frequency of 0% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Uncertain Significance. As this variant lies in splice region, additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2023	This sequence change affects codon 365 of the PLOD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PLOD1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Ehlers-Danlos syndrome, type VI (EDS VI) (PMID: 10874315, 21699693, 32381727, 35252061). This variant is also known as c.1119C>T. ClinVar contains an entry for this variant (Variation ID: 580535). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 35252061). For these reasons, this variant has been classified as Pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.1095C>T variant (also known as p.G365G), located in coding exon 10 of the PLOD1 gene, results from a C to T substitution at nucleotide position 1095. This nucleotide substitution does not change the at codon 365. This alteration, which is also known as c.1119C>T, has been reported as homozygous in an individuals with concerns for autosomal recessive kyphoscoliotic Ehlers-Danlos syndrome (EDS type VI) (Rohrbach M et al. Orphanet J Rare Dis, 2011 Jun;6:46; Zhao S et al. J Med Genet, 2021 Jan;58:41-47; Yan X et al. Front Pediatr, 2022 Feb;10:813758). Additionally, this alteration has been noted with a second PLOD1 alteration (phase unknown) in another individual with a clinical diagnosis of EDS type VI (Yeowell HN et al. Hum Mutat, 2000 Jul;16:90). RNA studies showed complete aberrant splicing (Yan X et al. Front Pediatr, 2022 Feb;10:813758). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includessplice predictorsand evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10686424, 21699693, 10874315) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

Cadd

Pathogenic

Dann

Benign

0.97

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.97

Position offset: -2

DS_DL_spliceai

0.53

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.

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