2-188995074-G-C

Variant names:

• chr2-188995074-G-C
• rs1057524653
• NM_000090.4:c.1484G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000090.4(COL3A1):​c.1484G>C​(p.Gly495Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G495E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.17
• Publications: 3 publications found

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]

COL3A1 Gene-Disease associations (from GenCC):

• autosomal dominant Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000090.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-188995074-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 459763.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-188995074-G-C is Pathogenic according to our data. Variant chr2-188995074-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 392836.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1484G>C	p.Gly495Ala	missense_variant	Exon 21 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1484G>C	p.Gly495Ala	missense_variant	Exon 21 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1385G>C	p.Gly462Ala	missense_variant	Exon 20 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.1484G>C	p.Gly495Ala	missense_variant	Exon 21 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.1484G>C	p.Gly495Ala	missense_variant	Exon 21 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 18, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G495A variant in the COL3A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G495A variant is not observed in large population cohorts (Lek et al., 2016). The G495A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this variant results in substitution of a Glycine residue in the Gly-X-Y repetitive motif of the triple helical region of the COL3A1 gene. In this domain, the Glycine in the triplet repeat is critical for protein folding, and substitution of a triplet Glycine is a known pathogenic mechanism (Stenson et al., 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (G492R, G492E, G492V, G498D) have been reported in the Human Gene Mutation Database in association with Ehlers-Danlos syndrome IV (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G495A as a likely pathogenic variant that may explain the pes planus reported in this individual. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H
PhyloP100		5.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.99		Loss of catalytic residue at G495 (P = 0.0706);Loss of catalytic residue at G495 (P = 0.0706);
MVP		0.98
MPC		0.68
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057524653; hg19: chr2-189859800; COSMIC: COSV58591490; COSMIC: COSV58591490;