rs149425237

Positions:

• chr1-11972896-G-A
• chr1-11972896-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1 PM2 BP4_Moderate BP6 BS1

The NM_000302.4(PLOD1):​c.1927G>A​(p.Val643Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,613,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V643V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 9.99

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a domain Fe2OG dioxygenase (size 91) in uniprot entity PLOD1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_000302.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24514475).
• BP6: Variant 1-11972896-G-A is Benign according to our data. Variant chr1-11972896-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263957.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}. Variant chr1-11972896-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00069 (105/152192) while in subpopulation NFE AF= 0.0011 (75/68018). AF 95% confidence interval is 0.000902. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.1927G>A	p.Val643Ile	missense_variant	18/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.2068G>A	p.Val690Ile	missense_variant	19/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.1927G>A	p.Val643Ile	missense_variant	18/19	1	NM_000302.4	ENSP00000196061.4
PLOD1	ENST00000481933.1	n.1354G>A		non_coding_transcript_exon_variant	1/2	2
PLOD1	ENST00000491536.5	n.384-2387G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000533 AC: 134 AN: 251478 Hom.: 1 AF XY: 0.000574 AC XY: 78 AN XY: 135916

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000958

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000937 AC: 1370 AN: 1461788 Hom.: 1 Cov.: 31 AF XY: 0.000897 AC XY: 652 AN XY: 727208

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.000591 AC XY: 44 AN XY: 74388

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000854 Hom.: 1

Bravo AF: 0.000710

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2021	The PLOD1 c.1927G>A; p.Val643Ile variant (rs149425237) is reported in the literature in a family affected with high myopia, though it was not demonstrated to be disease-causing (Kloss 2017). This variant is reported in ClinVar (Variation ID: 263957) and is found in the general population with an overall allele frequency of 0.05% (152/282864 alleles, including one homozygote) in the Genome Aggregation Database. The valine at codon 643 is highly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.488). However, given the lack of clinical and functional data, the significance of the p.Val643Ile variant is uncertain at this time. References: Kloss BA et al. Exome Sequence Analysis of 14 Families With High Myopia. Invest Ophthalmol Vis Sci. 2017 Apr 1;58(4):1982-1990. PMID: 28384719. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 08, 2021	PLOD1 NM_000302.3 exon 18 p.Val643Ile (c.1927G>A): This variant has been reported in the literature in one individual with high myopia (Kloss 2017 PMID:28384719). However, this variant is also present in 0.1% (75/68026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-11972896-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:263957). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2020	This variant is associated with the following publications: (PMID: 28384719) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PLOD1: PP3, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 30, 2024

Variant summary: PLOD1 c.1927G>A (p.Val643Ile) results in a conservative amino acid change located in the oxoglutarate/iron-dependent dioxygenase domain (IPR005123) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This frequency is not significantly higher than estimated for a pathogenic variant in PLOD1 causing Ehlers-Danlos Syndrome Type VI (0.00091 vs 0.0016), allowing no conclusion about variant significance. c.1927G>A has been reported in the literature in at least one family affected with high myopia (Kloss_2017) and an individual with pediatric myoamoya angiopathy who also had a pathogenic varinat in NF1 (Zanoni_2023), however these report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome Type VI. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28384719, 37012328). ClinVar contains an entry for this variant (Variation ID: 263957). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2021

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.90
MPC		0.70
ClinPred		0.087	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.54

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: rs149425237; hg19: chr1-12032953; COSMIC: COSV52144042;