Submissions for variant NM_000090.4(COL3A1):c.3607G>A (p.Ala1203Thr)

gnomAD frequency: 0.00004  dbSNP: rs550665335

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507021	SCV000603144	uncertain significance	not specified	2017-02-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530078	SCV000631667	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1203 of the COL3A1 protein (p.Ala1203Thr). This variant is present in population databases (rs550665335, gnomAD 0.01%). This missense change has been observed in individual(s) with a dissection of the hepatic artery, joint hypermobility and skin hyperelasticity (PMID: 25758994). ClinVar contains an entry for this variant (Variation ID: 439517). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV001176833	SCV001340894	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1203 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has also been identified in 9/282756 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507021	SCV001370644	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.3607G>A (p.Ala1203Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251358 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.3607G>A has been reported in the literature in one individual affected with dissection of the hepatic artery, joint hypermobility and skin fragility and hyperelasticity (Frank_2015). The report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25758994). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508129	SCV001714071	uncertain significance	not provided	2020-08-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001508129	SCV001747997	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001508129	SCV001812767	uncertain significance	not provided	2024-06-14	criteria provided, single submitter	clinical testing	A published functional study suggested this variant may result in decreased production and delayed electrophoretic mobility of type III collagen (PMID: 34318601); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 34318601, 25758994)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001508129	SCV004026424	uncertain significance	not provided	2023-06-26	criteria provided, single submitter	clinical testing	PM2_SUP, PP2
All of Us Research Program, National Institutes of Health	RCV000530078	SCV004824926	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1203 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has also been identified in 9/282756 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.