Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000414364 | SCV000490918 | uncertain significance | not provided | 2016-12-12 | criteria provided, single submitter | clinical testing | The c.4254+3A>G variant in the COL3A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to damage or destroy the splice donor site in intron 50, and may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.4254+3A>G variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.4254+3A>G as a variant of uncertain significance. |
Labcorp Genetics |
RCV000794942 | SCV000934379 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 50 of the COL3A1 gene. It does not directly change the encoded amino acid sequence of the COL3A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376799861, gnomAD 0.006%). This variant has been observed in individuals with clinical features of COL3A1-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372575). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Center for Genomics, |
RCV000794942 | SCV001190436 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2019-08-13 | criteria provided, single submitter | clinical testing | COL3A1 NM_000090.3 exon 50 c.4254+3A>G: This variant has not been reported in the literature but is present in 0.005% (2/34588) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189875619-A-G). This variant is present in ClinVar (Variation ID:372575). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence, but splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. |
Color Diagnostics, |
RCV001187661 | SCV001354520 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-06-29 | criteria provided, single submitter | clinical testing | This variant causes an A to G nucleotide substitution at the +3 position of intron 50 of the COL3A1 gene. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 6/251146 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. |
Mayo Clinic Laboratories, |
RCV000414364 | SCV001714072 | uncertain significance | not provided | 2021-06-17 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001187661 | SCV002627019 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2024-12-10 | criteria provided, single submitter | clinical testing | The c.4254+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 50 in the COL3A1 gene. This variant was identified in one or more individuals with features consistent with vascular Ehlers-Danlos syndrome (EDS) and segregated with disease in at least one family (external communication). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. |
Center for Genomics, |
RCV003224269 | SCV003919824 | uncertain significance | Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome | 2021-03-30 | criteria provided, single submitter | clinical testing | COL3A1 NM_000090.3 exon 50 c.4254+3A>G: This variant has not been reported in the literature but is present in 0.005% (2/34588) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189875619-A-G). This variant is present in ClinVar (Variation ID:372575). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence, but splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. |