2-189006354-G-T

Variant names:

• chr2-189006354-G-T
• rs587779704
• NM_000090.4:c.3103G>T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000090.4(COL3A1):​c.3103G>T​(p.Gly1035Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1035V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-189006355-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the COL3A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 4.0879 (above the threshold of 3.09). Trascript score misZ: 4.5995 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.996
• PP5: Variant 2-189006354-G-T is Pathogenic according to our data. Variant chr2-189006354-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.3103G>T	p.Gly1035Cys	missense_variant	Exon 43 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.3103G>T	p.Gly1035Cys	missense_variant	Exon 43 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.3004G>T	p.Gly1002Cys	missense_variant	Exon 42 of 50	1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:2

Jan 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in an individual affected with Ehlers–Danlos syndrome (PMID: 10706896). This variant is also known as G868C in the literature. ClinVar contains an entry for this variant (Variation ID: 101467). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 1035 of the COL3A1 protein (p.Gly1035Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. -

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Collagen Diagnostic Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial aortopathy Pathogenic:1

Nov 06, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The COL3A1 c.3103G>T (p.Gly1035Cys) variant involves the alteration of a conserved nucleotide and a critical amino acid. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 246170 control chromosomes in gnomAD. This variant was reported in one ED patient and was associated with arterial complications (Pepin_2000). In addition, one clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.6	H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Loss of methylation at R1034 (P = 0.052);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		1.0

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: rs587779704; hg19: chr2-189871080;