chr2-188999560-G-A

Position:

• chr2-188999560-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000304636.9(COL3A1):​c.2212G>A​(p.Gly738Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G738C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 ENST00000304636.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.13

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000304636.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-188999560-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1787788.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 2-188999560-G-A is Pathogenic according to our data. Variant chr2-188999560-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2212G>A	p.Gly738Ser	missense_variant	31/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2212G>A	p.Gly738Ser	missense_variant	31/51	1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.2113G>A	p.Gly705Ser	missense_variant	30/50	1		ENSP00000415346

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 26, 2016	This variant has been reported in individuals and families affected with Ehlers-Danlos syndrome (PMID: 10051163, 24922459). This variant is also known as p.Gly571Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 17227). Glycine residues within the triple helix region are important for fibrillar collagens structure and stability (PMID: 7695699, 19344236). In the case of COL3A1, the majority of the missense substitutions at the triple helix domain affect glycine residues (PMID: 24922459, 25758994). This variant is not present in population databases (rs121912925, ExAC no frequency). This sequence change replaces glycine with serine at codon 738 of the COL3A1 protein (p.Gly738Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Collagen Diagnostic Laboratory, University of Washington	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 10706896, 24922459, 9036918, 10051163, 25355833, 29650765) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	1.0
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.99		Gain of phosphorylation at G738 (P = 0.0033);Gain of phosphorylation at G738 (P = 0.0033);
MVP		0.99
MPC		0.62
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121912925; hg19: chr2-189864286;