1-11934766-CCCATACCTCGG-C

Position:

chr1-11934766-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]

PLOD1 links:

Genome browser will be placed here

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
PLOD1	NM_000302.4 link	c.-9_2delACCTCGGCCAT	p.Met1fs	frameshift_variant, start_lost	1/19	ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_000302.4 link	c.-9_2delACCTCGGCCAT		5_prime_UTR_variant	1/19	ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_001316320.2 link	c.-9_2delACCTCGGCCAT	p.Met1fs	frameshift_variant, start_lost	1/20		NP_001303249.1	Q02809-2
PLOD1	NM_001316320.2 link	c.-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
PLOD1	ENST00000196061.5 link	c.-9_2delACCTCGGCCAT	p.Met1fs	frameshift_variant, start_lost	1/19	1	NM_000302.4	ENSP00000196061.4		Q02809-1
PLOD1	ENST00000196061 link	c.-9_2delACCTCGGCCAT		5_prime_UTR_variant	1/19	1	NM_000302.4	ENSP00000196061.4		Q02809-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152208

Hom.:

Cov.:

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.:

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:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

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.:

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 submitter	clinical testing	GeneDx	Sep 19, 2024	Has 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 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PLOD1: PM2, BP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 18, 2024

Variant 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 submitter

clinical testing

Ambry Genetics

May 08, 2023

The 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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over