2-189002305-G-A

Position:

• chr2-189002305-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000090.4(COL3A1):​c.2399G>A​(p.Arg800Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.88

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ 4.0879 (greater than the threshold 3.09). Trascript score misZ 4.5995 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2399G>A	p.Arg800Lys	missense_variant	35/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2399G>A	p.Arg800Lys	missense_variant	35/51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.2300G>A	p.Arg767Lys	missense_variant	34/50	1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 02, 2023

The COL3A1 c2399G>A; p.Arg800Lys variant (rs199564715), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 459774). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.461). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Ehlers-Danlos syndrome, type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces arginine with lysine at codon 800 of the COL3A1 protein (p.Arg800Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with COL3A1-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 disruptive. 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	0.19
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	-0.085	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;T
Sift4G	Benign	0.092	T;T
Polyphen		0.98	D;.
Vest4		0.50
MutPred		0.31		Gain of glycosylation at R800 (P = 0.0036);Gain of glycosylation at R800 (P = 0.0036);
MVP		0.85
MPC		0.63
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199564715; hg19: chr2-189867031;