2-188997376-C-T

Variant names:

• chr2-188997376-C-T
• rs373838193
• NM_000090.4:c.1856C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP6 BS1 BS2

The NM_000090.4(COL3A1):​c.1856C>T​(p.Pro619Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000182 in 1,613,526 control chromosomes in the GnomAD database, including 2 homozygotes. 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. P619H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 4.09
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000090.4
• 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.
• BP6: Variant 2-188997376-C-T is Benign according to our data. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057. Variant chr2-188997376-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 333057.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00019 (277/1461510) while in subpopulation NFE AF = 0.000245 (272/1111668). AF 95% confidence interval is 0.000221. There are 2 homozygotes in GnomAdExome4. There are 148 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1856C>T	p.Pro619Leu	missense_variant	Exon 26 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1856C>T	p.Pro619Leu	missense_variant	Exon 26 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1757C>T	p.Pro586Leu	missense_variant	Exon 25 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.1703C>T	p.Pro568Leu	missense_variant	Exon 24 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.1856C>T	p.Pro619Leu	missense_variant	Exon 26 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152016 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251170 AF XY: 0.0000589

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 277 AN: 1461510 Hom.: 2 Cov.: 33 AF XY: 0.000204 AC XY: 148 AN XY: 727078

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000245 AC: 272 AN: 1111668

Other (OTH) AF: 0.0000662 AC: 4 AN: 60388

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152016 Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6 AN XY: 74234

African (AFR) AF: 0.0000967 AC: 4 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000665 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Uncertain:3 Benign:1

Aug 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Found in patient having exome sequencing for an unrelated indication. No known history of Ehlers-Danlos syndrome, type IV -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 619 of the COL3A1 protein (p.Pro619Leu). This variant is present in population databases (rs373838193, gnomAD 0.008%). 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: 333057). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. 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. -

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 619 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 12/282552 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

May 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 619 of the COL3A1 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with small vessel disease and stroke (PMID: 31719132). This variant has been identified in 12/282552 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -

not specified Uncertain:1

Apr 16, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL3A1 c.1856C>T (p.Pro619Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251170 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL3A1 causing Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, allowing no conclusion about variant significance. c.1856C>T has been observed in one individual affected with small vessel disease, without strong evidence for causality (Tan_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31719132). ClinVar contains an entry for this variant (Variation ID: 333057). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Apr 30, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with small vessel disease (PMID: 31719132); however, detailed clinical information was not provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 31719132) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.76	N;N
PhyloP100		4.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.012	D;T
Polyphen		0.99	D;.
Vest4		0.44
MVP		0.76
MPC		0.64
ClinPred		0.86	D
GERP RS		6.2
Varity_R		0.25
gMVP		0.54
Mutation Taster		=23/77	disease causing

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: rs373838193; hg19: chr2-189862102;