NM_000302.4:c.1117C>T

Variant names:

• chr1-11963551-C-T
• rs750301725
• NM_000302.4:c.1117C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_000302.4(PLOD1):​c.1117C>T​(p.Arg373Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000525 in 1,601,302 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000051 (1 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.495

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1809499).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000511 (74/1449148) while in subpopulation SAS AF= 0.000515 (43/83532). AF 95% confidence interval is 0.000393. There are 1 homozygotes in gnomad4_exome. There are 41 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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 rank	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.1117C>T	p.Arg373Cys	missense_variant	Exon 11 of 19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.1258C>T	p.Arg420Cys	missense_variant	Exon 12 of 20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.1117C>T	p.Arg373Cys	missense_variant	Exon 11 of 19	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000873 AC: 20 AN: 229068 Hom.: 0 AF XY: 0.0000730 AC XY: 9 AN XY: 123310

Gnomad AFR exome AF: 0.0000692

Gnomad AMR exome AF: 0.0000628

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000543

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000964

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.0000511 AC: 74 AN: 1449148 Hom.: 1 Cov.: 31 AF XY: 0.0000570 AC XY: 41 AN XY: 719458

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000707

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000515

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152154 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74322

Gnomad4 AFR AF: 0.000241

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000989 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1117C>T (p.R373C) alteration is located in exon 11 (coding exon 11) of the PLOD1 gene. This alteration results from a C to T substitution at nucleotide position 1117, causing the arginine (R) at amino acid position 373 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Mar 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1

Aug 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with cysteine at codon 373 of the PLOD1 protein (p.Arg373Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs750301725, ExAC 0.08%). This variant has not been reported in the literature in individuals affected with PLOD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.034	D
Polyphen		0.66	P
Vest4		0.47
MVP		0.92
MPC		0.42
ClinPred		0.074	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.50

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: rs750301725; hg19: chr1-12023608; COSMIC: COSV52145367; COSMIC: COSV52145367;