ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.3938A>G (p.Lys1313Arg) (rs111840783)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000514567 SCV000883646 benign not provided 2018-01-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000181114 SCV000318113 likely benign Cardiovascular phenotype 2017-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Blueprint Genetics, RCV000157142 SCV000206865 uncertain significance Loeys-Dietz syndrome 2014-08-01 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770605 SCV000902055 benign Thoracic aortic aneurysm and aortic dissection 2016-08-31 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148461 SCV000190160 uncertain significance Ehlers-Danlos syndrome, type 4 2014-06-01 no assertion criteria provided research
CSER_CC_NCGL; University of Washington Medical Center RCV000148461 SCV000503567 uncertain significance Ehlers-Danlos syndrome, type 4 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing for an unrelated indication. No known history of Ehlers-Danlos syndrome, type IV
Center for Human Genetics, Inc RCV000659433 SCV000781247 uncertain significance Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514567 SCV000609767 likely benign not provided 2017-05-19 criteria provided, single submitter clinical testing
Color RCV000770605 SCV000911140 likely benign Thoracic aortic aneurysm and aortic dissection 2018-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000417378 SCV000233390 likely benign not specified 2017-10-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV000148461 SCV000425545 likely benign Ehlers-Danlos syndrome, type 4 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000417378 SCV000919242 benign not specified 2018-05-14 criteria provided, single submitter clinical testing 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.
Invitae RCV000148461 SCV000554703 likely benign Ehlers-Danlos syndrome, type 4 2017-11-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000417378 SCV000538718 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000664303 SCV000788232 benign Ehlers-Danlos syndrome 2018-04-01 criteria provided, single submitter research 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.

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