rs138490756

chr1-11965543-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000302.4(PLOD1):c.1534C>T(p.Arg512Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,613,664 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R512H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.357

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013092965).
• BP6: Variant 1-11965543-C-T is Benign according to our data. Variant chr1-11965543-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255801.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=2}. Variant chr1-11965543-C-T is described in Lovd as [Likely_benign]. Variant chr1-11965543-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00321 (489/152270) while in subpopulation NFE AF= 0.00572 (389/68024). AF 95% confidence interval is 0.00525. There are 2 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4	c.1534C>T	p.Arg512Cys	missense_variant	14/19	ENST00000196061.5
PLOD1	NM_001316320.2	c.1675C>T	p.Arg559Cys	missense_variant	15/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5	c.1534C>T	p.Arg512Cys	missense_variant	14/19	1	NM_000302.4	P1
PLOD1	ENST00000470133.1	n.148C>T		non_coding_transcript_exon_variant	2/3	3
PLOD1	ENST00000491536.5	n.162C>T		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152152 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00312 AC: 784 AN: 251210 Hom.: 1 AF XY: 0.00332 AC XY: 451 AN XY: 135844

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00323

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00486

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00490 AC: 7156 AN: 1461394 Hom.: 27 Cov.: 31 AF XY: 0.00487 AC XY: 3538 AN XY: 726980

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00349

Gnomad4 FIN exome AF: 0.00280

Gnomad4 NFE exome AF: 0.00566

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00321 AC: 489 AN: 152270 Hom.: 2 Cov.: 31 AF XY: 0.00275 AC XY: 205 AN XY: 74454

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00572

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00444 Hom.: 5

Bravo AF: 0.00294

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00528

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PLOD1 NM_000302.3 exon 14 p.Arg512Cys (c.1534C>T): This variant has not been reported in the literature, but it is present in 0.5% (653/126532) of European alleles, including one homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-12025600-C-T). This variant is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID: 255801). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant are insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2023	Variant summary: PLOD1 c.1534C>T (p.Arg512Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 251210 control chromosomes, predominantly at a frequency of 0.0049 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PLOD1 causing Ehlers-Danlos Syndrome Type VI phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1534C>T in individuals affected with Ehlers-Danlos Syndrome Type VI and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=8) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PLOD1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2021	This variant is associated with the following publications: (PMID: 16758144, 14565595) -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.90	D;D
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.94	P
Vest4		0.43
MVP		0.86
MPC		0.42
ClinPred		0.030	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.64

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: rs138490756; hg19: chr1-12025600;