1-11934782-G-A

Variant names:

• chr1-11934782-G-A
• NM_000302.4:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

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. Variant has been reported in ClinVar as Pathogenic (★).

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, kyphoscoliotic type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 21 pathogenic variants. Next in-frame start position is after 223 codons. Genomic position: 11956940. Lost 0.305 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-11934782-G-A is Pathogenic according to our data. Variant chr1-11934782-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3667487.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30854

American (AMR) AF: 0.00 AC: 0 AN: 35534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25006

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35288

South Asian (SAS) AF: 0.00 AC: 0 AN: 78616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5022

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077462

Other (OTH) AF: 0.00 AC: 0 AN: 57676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.2
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
PromoterAI		-0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.70
Mutation Taster		=24/176	disease causing

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

Other links and lift over

hg19: chr1-11994839;