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 NM_000302.4(PLOD1):​c.1533C>G​(p.Tyr511*) 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 NM_000302.4 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]

PLOD1 (HGNC:):

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.Tyr511*	stop_gained	14/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.1674C>G	p.Tyr558*	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.Tyr511*	stop_gained	14/19	1	NM_000302.4	ENSP00000196061.4
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	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	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, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2020	- -

Ehlers-Danlos syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 15, 2021	- -
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. -

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

Nov 12, 2024

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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
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;