rs121913552

Positions:

• chr1-11965542-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000196061.5(PLOD1):​c.1533C>G​(p.Tyr511Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PLOD1 ENST00000196061.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 2.13

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 18 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 1-11965542-C-G is Pathogenic according to our data. Variant chr1-11965542-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 14370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11965542-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.1533C>G	p.Tyr511Ter	stop_gained	14/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.1674C>G	p.Tyr558Ter	stop_gained	15/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.1533C>G	p.Tyr511Ter	stop_gained	14/19	1	NM_000302.4	ENSP00000196061	P1
PLOD1	ENST00000470133.1	n.147C>G		non_coding_transcript_exon_variant	2/3	3
PLOD1	ENST00000491536.5	n.161C>G		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251214 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 727036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152154 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Tyr511*) in the PLOD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLOD1 are known to be pathogenic (PMID: 10874315, 21699693). This variant is present in population databases (rs121913552, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome type VI (PMID: 9220536, 10329027). ClinVar contains an entry for this variant (Variation ID: 14370). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 4-year-old female with tall habitus, hyperextensibility, hip dysplasia, mild scoliosis, lumbar kyphosis, arachnodactyly, fragile connective tissue, motor delays, hypotonia, dysmorphisms, tethered cord, eye anomalies -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -

Ehlers-Danlos syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2019	The p.Tyr511X variant in PLOD1 has been reported in 2 homozygous and 2 compound heterozygous individuals with Ehlers-Danlos syndrome type VI (Walker 1999, Yeowell and Walker 1997, Yeowell 2000). It has also been identified in 2/128944 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 14370). This nonsense variant leads to a premature termination codon at position 511, which is predicted to lead to a truncated or absent protein. Loss of function of the PLOD1 gene is strongly associated with autosomal recessive Ehlers-Danlos syndrome type VI. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Ehlers-Danlos syndrome type VI. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 15, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies performed on patient fibroblasts demonstrated this variant may result in exon skipping, which results in a truncated protein product missing the 38 amino acids encoded by exon 14, and results in significantly reduced lysyl hydroxylase activity (Walker et al., 1999; Pousi et al., 2000; Yeowell et al., 2000); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301635, 25525159, 9220536, 10329027, 10729709, 10874315, 31345219) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 19, 2022	PP4, PM3_strong, PS3, PS4, PVS1 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2020

The p.Y511* pathogenic mutation (also known as c.1533C>G), located in coding exon 14 of the PLOD1 gene, results from a C to G substitution at nucleotide position 1533. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This alteration has been reported in patients with kyphoscoliotic Ehlers-Danlos syndrome (Yeowell HN et al. Proc. Assoc. Am. Physicians, 1997 Jul;109:383-96; Walker LC et al. Mol. Genet. Metab., 1999 May;67:74-82). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

PLOD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The PLOD1 c.1533C>G variant is predicted to result in premature protein termination (p.Tyr511*). This variant was reported, along with another pathogenic variant, in an individual with Ehlers-Danlos syndrome VI (Yeowell et al. 1997. PubMed ID: 9220536). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Nonsense variants in PLOD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	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: rs121913552; hg19: chr1-12025599;