1-11934782-G-A

Position:

• chr1-11934782-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000302.4(PLOD1):​c.3G>A​(p.Met1?) variant causes a start lost 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLOD1 NM_000302.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000302.4 (PLOD1) was described as [Pathogenic] in ClinVar as 3371745
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.3G>A	p.Met1?	start_lost	1/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.3G>A	p.Met1?	start_lost	1/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.3G>A	p.Met1?	start_lost	1/19	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.22e-7 AC: 1 AN: 1385642 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000283

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2024

This sequence change affects the initiator methionine of the PLOD1 mRNA. The next in-frame methionine is located at codon 223. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (PMID: 34161861). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant disrupts a region of the PLOD1 protein in which other variant(s) (p.Leu85Pro) have been determined to be pathogenic (PMID: 21699693). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	-0.16	T
PROVEAN	Benign	-0.96	N;N;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.078	T;T;T
Polyphen		0.53	.;.;P
Vest4		0.75
MutPred		0.66		Gain of catalytic residue at L6 (P = 0.0245);Gain of catalytic residue at L6 (P = 0.0245);Gain of catalytic residue at L6 (P = 0.0245);
MVP		0.80
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.70

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: chr1-11994839;