1-11934766-CCCATACCTCGG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1PS1_ModeratePM2BS1_Supporting

The NM_000302.4(PLOD1):​c.-9_2delACCTCGGCCAT​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,534,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 frameshift, start_lost

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.687
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 59 pathogenic variants in the truncated region.
PS1
Another start lost variant in NM_000302.4 (PLOD1) was described as [Pathogenic] in ClinVar as 3371745
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00031 (429/1382726) while in subpopulation NFE AF= 0.000376 (405/1076966). AF 95% confidence interval is 0.000346. There are 0 homozygotes in gnomad4_exome. There are 198 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLOD1NM_000302.4 linkc.-9_2delACCTCGGCCAT p.Met1fs frameshift_variant, start_lost 1/19 ENST00000196061.5 NP_000293.2 Q02809-1
PLOD1NM_000302.4 linkc.-9_2delACCTCGGCCAT 5_prime_UTR_variant 1/19 ENST00000196061.5 NP_000293.2 Q02809-1
PLOD1NM_001316320.2 linkc.-9_2delACCTCGGCCAT p.Met1fs frameshift_variant, start_lost 1/20 NP_001303249.1 Q02809-2
PLOD1NM_001316320.2 linkc.-9_2delACCTCGGCCAT 5_prime_UTR_variant 1/20 NP_001303249.1 Q02809-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLOD1ENST00000196061.5 linkc.-9_2delACCTCGGCCAT p.Met1fs frameshift_variant, start_lost 1/191 NM_000302.4 ENSP00000196061.4 Q02809-1
PLOD1ENST00000196061 linkc.-9_2delACCTCGGCCAT 5_prime_UTR_variant 1/191 NM_000302.4 ENSP00000196061.4 Q02809-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000310
AC:
429
AN:
1382726
Hom.:
0
AF XY:
0.000290
AC XY:
198
AN XY:
682332
show subpopulations
Gnomad4 AFR exome
AF:
0.0000327
Gnomad4 AMR exome
AF:
0.00
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:
0.000376
Gnomad4 OTH exome
AF:
0.000400
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000117

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024PLOD1: PM2, BP4 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 19, 2024Has not been previously published as pathogenic or benign to our knowledge; Alters the Kozak sequence, which plays a major role in the initiation of translation -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 18, 2024Variant summary: PLOD1 c.-9_2del11 is a small deletion located in the 5' untranslated region and the first coding exon. It encompasses the first two nucleotides of the start codon. However, the remaining upstream nucleotides restore the sequence of the start codon, likely maintaining the original reading frame. This indicates the variant is less likely to be associated with disease, however functional studies have not been performed. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.-9_2del11 in individuals affected with Ehlers-Danlos Syndrome Type VI and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 422689). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 08, 2023The c.-9_2del11 variant (also known as p.M1?), located in the 5' untranslated region (5'UTR) and coding exon 1 of the PLOD1 gene, results from a deletion of 11 nucleotides between positions -9 and 2. This deletion interrupts the native ATG initiation codon; however, the remaining realigned nucleotides recreate an ATG initiation codon at the same position and is predicted to maintain the normal reading frame. However, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747037908; hg19: chr1-11994823; API