rs1057518879

Positions:

• chr1-11965571-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000302.4(PLOD1):​c.1562G>A​(p.Trp521Ter) variant causes a stop gained change involving the alteration of a 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLOD1 NM_000302.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 10.0

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-11965571-G-A is Pathogenic according to our data. Variant chr1-11965571-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 374077.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4	c.1562G>A	p.Trp521Ter	stop_gained	14/19	ENST00000196061.5
PLOD1	NM_001316320.2	c.1703G>A	p.Trp568Ter	stop_gained	15/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5	c.1562G>A	p.Trp521Ter	stop_gained	14/19	1	NM_000302.4	P1
PLOD1	ENST00000470133.1	n.176G>A		non_coding_transcript_exon_variant	2/3	3
PLOD1	ENST00000491536.5	n.190G>A		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Umbilical hernia;C0020255:Hydrocephalus;C0221358:Dolichocephaly;C0426790:Narrow chest;C1836599:Macrocephaly at birth;C1837397:Severe global developmental delay;C2267233:Neonatal hypotonia;C4082172:Porencephalic cyst Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Feeding difficulties;C0431659:Hypoplasia of scrotum;C0431663:Bilateral cryptorchidism;C1844820:Joint hypermobility;C1845123:Generalized neonatal hypotonia;C3697248:Short chin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

High palate;C0749379:Thoracolumbar scoliosis;C0795690:Congenital omphalocele;C1836542:Depressed nasal bridge;C1844820:Joint hypermobility;C1858120:Generalized hypotonia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs1057518879; hg19: chr1-12025628;