1-11957924-G-C

Variant names:

• chr1-11957924-G-C
• rs184999645
• NM_000302.4:c.824G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001316320.2(PLOD1):​c.965G>C​(p.Arg322Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R322C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLOD1 NM_001316320.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316320.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	NM_000302.4	MANE Select	c.824G>C	p.Arg275Pro	missense	Exon 8 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.965G>C	p.Arg322Pro	missense	Exon 9 of 20	NP_001303249.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.824G>C	p.Arg275Pro	missense	Exon 8 of 19	ENSP00000196061.4
	PLOD1	ENST00000854019.1		c.968G>C	p.Arg323Pro	missense	Exon 9 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.911G>C	p.Arg304Pro	missense	Exon 9 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.2
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.31
Sift	Benign	0.098	T
Sift4G	Uncertain	0.046	D
Polyphen		0.96	D
Vest4		0.52
MVP		0.89
MPC		0.47
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.55
gMVP		0.89
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs184999645; hg19: chr1-12017981;