2-189043249-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_StrongBS1_SupportingBS2

The NM_000393.5(COL5A2):c.3373G>A(p.Gly1125Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,459,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 7.88

Publications

0 publications found

Variant links:

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

COL5A2 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome, classic type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Ehlers-Danlos syndrome, classic type, 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

COL5A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000514 (75/1459300) while in subpopulation NFE AF = 0.0000667 (74/1109812). AF 95% confidence interval is 0.0000543. There are 0 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A2	NM_000393.5 link	c.3373G>A	p.Gly1125Arg	missense_variant	Exon 48 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4 link	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 51 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 53 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 52 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 link	c.3373G>A	p.Gly1125Arg	missense_variant	Exon 48 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1 link	c.2212G>A	p.Gly738Arg	missense_variant	Exon 41 of 47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250906

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1459300

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000667

AC:

AN:

1109812

Other (OTH)

AF:

0.0000166

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Dec 30, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33974636) -

not specified

Uncertain:1

Jun 24, 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: COL5A2 c.3373G>A (p.Gly1125Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2.8e-05 in 250906 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3373G>A has been observed in individuals affected with Chiari Malformation Type 1 or early sudden unexplained death (Salfati_2019, Urbizu_2021). These reports do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos syndrome, classic type, 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31847883, 33974636). ClinVar contains an entry for this variant (Variation ID: 382848). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G1125R variant (also known as c.3373G>A), located in coding exon 48 of the COL5A2 gene, results from a G to A substitution at nucleotide position 3373. The glycine at codon 1125 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a sudden death cohort and a Ehlers-Danlos syndrome (EDS) genetic testing cohort (Salfati EL et al. Genome Med, 2019 Dec;11:83; Wilson GN et al. Curr Issues Mol Biol, 2024 Mar;46:2620-2643). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif of the triple helical domain in the COL5A2 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al.Science.1994;266:75-81; Hohenester E et al.Proc. Natl.Acad. Sci.U.S.A.2008;105:18273-7; Ambry internal data). Glycine substitutions in the triple helical domain of COL5A2 have been reported in association with classic Ehlers-Danlos syndrome (cEDS), but the number of affected individuals is limited and several other COL5A2 glycine substitutions in the triple helical domain (e.g., p.G951E and p.G831A) are too common for disease in population databases (Symoens S et al.Hum. Mutat., 2012 Oct;33:1485-93; Ritelli M et al.Orphanet J Rare Dis.2013 Apr;8:58).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Ehlers-Danlos syndrome, classic type, 2

Uncertain:1

Mar 14, 2023

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL5A2 c.3373G>A variant is classified as VUS (PM1, PM2, PP3) The COL5A2 c.3373G>A variant is a single nucleotide change in exon 48/54 of the COL5A2 gene, which is predicted to change the amino acid glycine at position 1125 in the protein to arginine. This variant is absent from population databases (PM2). This variant resides in a Collagen triple helix repeat region made of the repetitious amino acid sequence glycine - X - Y, where glycine substitutions are a common cause of disease (PM1). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs151187317) and has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 382848). This variant has been detected in HGMD with some degree of doubt over its disease association with a Chiari malformation(CM2115602). -

Ehlers-Danlos syndrome, classic type, 1

Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1125 of the COL5A2 protein (p.Gly1125Arg). This variant is present in population databases (rs151187317, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 382848). 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 expected to disrupt COL5A2 protein function with a positive predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;T;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.1

H;.;H

PhyloP100

7.9

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.2

D;.;.

REVEL

Pathogenic

1.0

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

1.0

D;.;D

Vest4

0.98

MutPred

0.99

Gain of MoRF binding (P = 0.0137);.;Gain of MoRF binding (P = 0.0137);

MVP

1.0

MPC

0.31

ClinPred

1.0

GERP RS

5.2

Varity_R

0.97

gMVP

0.98

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over