Submissions for variant NM_000090.4(COL3A1):c.2607T>A (p.Pro869=)

gnomAD frequency: 0.00001  dbSNP: rs376643618

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310838	SCV000318108	benign	Familial thoracic aortic aneurysm and aortic dissection	2022-05-26	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000418506	SCV000511700	uncertain significance	not provided	2016-11-10	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000608441	SCV000732471	likely benign	not specified	2018-02-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204079	SCV001375268	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-08-18	criteria provided, single submitter	clinical testing	This sequence change affects codon 869 of the COL3A1 mRNA. It is a 'silent' change, meaning that it does not 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 (rs376643618, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 263465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001204079	SCV002496068	uncertain significance	Ehlers-Danlos syndrome, type 4	2021-06-04	criteria provided, single submitter	clinical testing	COL3A1 NM_000090.3 exon 37 p.Pro869= (c.2607T>A): This variant has not been reported in the literature but is present in 0.002% (2/68028) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189003464-T-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:263465). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. Despite its position at the intron/exon juction, computational prediction tools do not suggest that it alters 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252067	SCV002522825	uncertain significance	See cases	2021-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002310838	SCV004362996	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608441	SCV004803437	benign	not specified	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.2607T>A (p.Pro869Pro) alters a non-conserved nucleotide located close to a canonical splice site, specifically the last nucleotide of exon 37, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.2e-05 in 1613292 control chromosomes (i.e., 36 alleles, no homozygotes; gnomAD v4.0.0). The observed variant frequency is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. c.2607T>A has been reported in the literature in at least one individual affected with breast cancer (e.g., Gomez-Flores-Ramos_2022), however without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. The following publication was ascertained in the context of this evaluation (PMID: 35406420). ClinVar contains an entry for this variant (Variation ID: 263465). Based on the evidence outlined above, the variant was classified as benign.
All of Us Research Program, National Institutes of Health	RCV001204079	SCV004826740	likely benign	Ehlers-Danlos syndrome, type 4	2023-12-01	criteria provided, single submitter	clinical testing