rs149425237

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

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

Scores

4
10
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 9.99

Publications

10 publications found
Variant links:
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 Gene-Disease associations (from GenCC):
  • Ehlers-Danlos syndrome, kyphoscoliotic type 1
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957. Variant chr1-11972896-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 263957.
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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLOD1NM_000302.4 linkc.1927G>A p.Val643Ile missense_variant Exon 18 of 19 ENST00000196061.5 NP_000293.2 Q02809-1
PLOD1NM_001316320.2 linkc.2068G>A p.Val690Ile missense_variant Exon 19 of 20 NP_001303249.1 Q02809-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLOD1ENST00000196061.5 linkc.1927G>A p.Val643Ile missense_variant Exon 18 of 19 1 NM_000302.4 ENSP00000196061.4 Q02809-1
PLOD1ENST00000481933.1 linkn.1354G>A non_coding_transcript_exon_variant Exon 1 of 2 2
PLOD1ENST00000491536.5 linkn.384-2387G>A intron_variant Intron 4 of 4 3

Frequencies

GnomAD3 genomes
AF:
0.000690
AC:
105
AN:
152074
Hom.:
0
Cov.:
31
show subpopulations
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
GnomAD2 exomes
AF:
0.000533
AC:
134
AN:
251478
AF XY:
0.000574
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33474
American (AMR)
AF:
0.000224
AC:
10
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.000197
AC:
17
AN:
86258
European-Finnish (FIN)
AF:
0.000206
AC:
11
AN:
53408
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00117
AC:
1302
AN:
1111936
Other (OTH)
AF:
0.000397
AC:
24
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
69
137
206
274
343
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
56
112
168
224
280
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000690
AC:
105
AN:
152192
Hom.:
0
Cov.:
31
AF XY:
0.000591
AC XY:
44
AN XY:
74388
show subpopulations
African (AFR)
AF:
0.000241
AC:
10
AN:
41532
American (AMR)
AF:
0.000917
AC:
14
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5180
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4820
European-Finnish (FIN)
AF:
0.000283
AC:
3
AN:
10586
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00110
AC:
75
AN:
68018
Other (OTH)
AF:
0.000473
AC:
1
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
7
14
22
29
36
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000896
Hom.:
2
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:6Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:3Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Mar 08, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 10, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

not provided Uncertain:1Benign:2
Dec 24, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28384719) -

Feb 22, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PLOD1: PP3, BS2 -

not specified Uncertain:1
Jul 07, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00091 in 1613980 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. 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. Co-occurrences with other pathogenic variant(s) have been reported (NF1 c.4971_4977del, p.(Tyr1657*)), providing supporting evidence for a benign role (Zanoni_2023). 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. -

Cardiovascular phenotype Uncertain:1
Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1
Apr 27, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
PhyloP100
10
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
Mutation Taster
=92/8
polymorphism

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

Other links and lift over

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