rs771858477

chr2-188990111-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000090.4(COL3A1):c.706C>T(p.Pro236Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P236L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.28

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000090.4
• PP2: Missense variant where missense usually causes diseases, COL3A1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.706C>T	p.Pro236Ser	missense_variant	9/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.706C>T	p.Pro236Ser	missense_variant	9/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.706C>T	p.Pro236Ser	missense_variant	9/50	1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250844 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461424 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces proline with serine at codon 236 of the COL3A1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/250844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 15, 2016	The p.P236S variant (also known as c.706C>T), located in coding exon 9 of the COL3A1 gene, results from a C to T substitution at nucleotide position 706. The proline at codon 236 is replaced by serine, an amino acid with some similar properties. This variant was previously reported in the SNPDatabase as rs771858477. Based on data from ExAC, the T allele has an overall frequency of <0.01% (3/105680). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2013

Pro236Ser (CCC>TCC): c.706 C>T in exon 9 of the COL3A1 gene (NM_000090.3). The Pro236Ser variant in the COL3A1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro236Ser results in a non-conservative amino acid substitution of a non-polar Proline with a neutral, polar Serine at a position that is conserved in mammals. The Pro236Ser variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations in nearby residues have been reported in association with Ehlers-Danlos syndrome (EDS), however, the majority of disease-causing missense mutations in the COL3A1 gene are Glycine substitutions in the Gly-X-Y repeats. Also, in silico analysis predicts Pro236Ser is benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if Pro236Ser is a disease-causing mutation or a rare benign variant. At least 95% of patients with autosomal dominant Ehlers-Danlos syndrome type IV have been reported to have a mutation in the COL3A1 gene (Pepin M et al., 2011). The variant is found in TAAD panel(s). -

Ehlers-Danlos syndrome, type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 236 of the COL3A1 protein (p.Pro236Ser). This variant is present in population databases (rs771858477, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199713). 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 not expected to disrupt COL3A1 protein function. 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. -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.42
Sift	Benign	0.090	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.040	B;.
Vest4		0.31
MutPred		0.41		Gain of phosphorylation at P236 (P = 0.0013);Gain of phosphorylation at P236 (P = 0.0013);
MVP		0.81
MPC		0.63
ClinPred		0.24	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.55

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: rs771858477; hg19: chr2-189854837;