ClinVar Genomic variation as it relates to human health

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.

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

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.

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.

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.

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.

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.

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