rs111840783

chr2-189010292-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS1

The NM_000090.4(COL3A1):c.3938A>G(p.Lys1313Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,614,080 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. K1313E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:12
• Conservation: PhyloP100: 7.50

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL3A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3177298).
• BP6: Variant 2-189010292-A-G is Benign according to our data. Variant chr2-189010292-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161218.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=7, Uncertain_significance=3}. Variant chr2-189010292-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000782 (119/152242) while in subpopulation NFE AF= 0.00138 (94/68044). AF 95% confidence interval is 0.00115. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.3938A>G	p.Lys1313Arg	missense_variant	49/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.3938A>G	p.Lys1313Arg	missense_variant	49/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.3839A>G	p.Lys1280Arg	missense_variant	48/50	1
COL3A1	ENST00000487010.1	n.1035A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000776 AC: 195 AN: 251428 Hom.: 0 AF XY: 0.000795 AC XY: 108 AN XY: 135894

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00158 AC: 2307 AN: 1461838 Hom.: 3 Cov.: 32 AF XY: 0.00155 AC XY: 1130 AN XY: 727218

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.000782 AC: 119 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74394

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.000903

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.000799 AC: 97

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Aug 01, 2016	Found in patient having exome sequencing for an unrelated indication. No known history of Ehlers-Danlos syndrome, type IV -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 10, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in gnomAD at a MaxMAF of 0.016% (199/126780 European chrs - high for disease incidence of 1/200,000). It has been classified in ClinVar with 1 star as VUS by GeneDx and CSER_CC_NCGL and as Likely benign by Ambry. It is present in HGMD in 4 papers - comments suggest VUS. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2018	Variant summary: COL3A1 c.3938A>G (p.Lys1313Arg) results in a conservative amino acid change located in the Fibrillar collagen, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 0.0008 in 277186 control chromosomes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1067-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.3938A>G, has been reported in the literature in individuals affected with Ehlers-Danlos Syndrome, Vascular Type. A publication, Stembridge_2015, cites the variant to occur in a patient and sister that did not present with features of vascular EDS, along with finding collagen and biochemistry to be normal. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2022	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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 07, 2018	- -

Ehlers-Danlos syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Feb 25, 2022	- -
Benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Apr 01, 2018	The COL3A1 variant designated as NM_000090.3:c.3938A>G (p.Lys1313Arg) is classified as likely benign. It is present in approximately 1/380 individuals of European non-Finnish ancestry (exac.broadinstitute.org). That is more common than any known aneurysm frequency, and as such, this variant can be excluded as a single cause for vascular Ehlers-Danlos syndrome. This high variant frequency may also explain reports of many previously tested individuals with vascular events who also have this variant. The crystal structure of the carboxyl-terminal propeptide of the proa1(III) chains encoded by COL3A1 has been well-defined. The COL3A1 p.Lys1313Arg variant is in the domain that directs chain-chain association. The residue is on an outward-facing region that does not participate in chain interaction and is predicted not to be involved in protein interaction (Stembridge et al, 2015 PMID:25846194). Wordsworth, Ogilvie, & Sykes (1991, PMID: 2049575) also looked at this region and found families in which the variant did not co-segregate with an aneurysm phenotype in the family, and the presence of the variant did not seem to exacerbate clinical symptoms. Stembridge et al (2015) described a family with the COL3A1 p. Lys1313Arg variant wherein the proband had a clinical appearance of Ehlers-Danlos syndrome, hypermobility type, and two relatives had a history of joint hypermobility. The association between the variant and the family’s phenotype of hypermobility was not defined. Patients with the COL3A1 p.Lys1313Arg variant who were tested at the UW Collagen Diagnostic Laboratory did not have clinical features that qualified them for a diagnosis of vascular Ehlers-Danlos syndrome, or had other variants associated with connective tissue disorders to account for their connective tissue phenotypes. The combined data provide weak evidence than the COL3A1 p.Lys1313Arg variant is likely benign in the context of vascular Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV). Several reports have described varying features in families with COL3A1 heterozygous missense variants (Leistritz et al., 2011, PMID:21637106, Cortini et al., 2017 PMID:28183226). Thus clinical associations other than those described in the literature cannot be excluded. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <0.1% probability of pathogenicity, which is consistent with a classification of benign. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Loeys-Dietz syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 01, 2014

- -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jan 05, 2022

COL3A1 NM_000090.3 exon 49 p.Lys1313Arg (c.3938A>G): This variant has been reported in the literature in two individuals with vascular anomalies (Pickup 2011 PMID: 21086191, Traenka 2019 PMID:31903434). However, this variant is also present in 0.1% (91/64586) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189010292-A-G?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:161218). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.047	D;D
Sift4G	Benign	0.21	T;T
Polyphen		1.0	D;.
Vest4		0.61
MVP		0.88
MPC		0.17
ClinPred		0.060	T
GERP RS		5.9
Varity_R		0.28
gMVP		0.65

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: rs111840783; hg19: chr2-189875018;