2-189004357-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000090.4(COL3A1):​c.2924G>T​(p.Gly975Val) 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. G975S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL3A1
NM_000090.4 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.70
Variant links:
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]

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ACMG classification

Classification made for transcript

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 chr2-189004356-G-A 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 2-189004357-G-T is Pathogenic according to our data. Variant chr2-189004357-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189004357-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL3A1NM_000090.4 linkc.2924G>T p.Gly975Val missense_variant Exon 40 of 51 ENST00000304636.9 NP_000081.2 P02461-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL3A1ENST00000304636.9 linkc.2924G>T p.Gly975Val missense_variant Exon 40 of 51 1 NM_000090.4 ENSP00000304408.4 P02461-1
COL3A1ENST00000450867.2 linkc.2825G>T p.Gly942Val missense_variant Exon 39 of 50 1 ENSP00000415346.2 H7C435

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:3
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PP3_Strong+PS4_Supporting+PM6_Supporting+PP4+PP2 -

May 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 975 of the COL3A1 protein (p.Gly975Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with vascular Ehlers-Danlos syndrome (PMID: 18043893, 30474650). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 101246). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL3A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL3A1. 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, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. -

-
Collagen Diagnostic Laboratory, University of Washington
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.6
H
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-6.4
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
0.99
D
Vest4
0.99
MutPred
1.0
Gain of ubiquitination at K977 (P = 0.1115);
MVP
0.99
MPC
1.8
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.97
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587779542; hg19: chr2-189869083; API