Submissions for variant NM_000090.4(COL3A1):c.1697C>T (p.Pro566Leu)

gnomAD frequency: 0.00011  dbSNP: rs150543864

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000308672	SCV000425514	benign	Ehlers-Danlos syndrome, type 4	2018-01-13	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000308672	SCV000756066	likely benign	Ehlers-Danlos syndrome, type 4	2025-01-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001178574	SCV001343045	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-10-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001178574	SCV002712764	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-06-08	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV004797804	SCV005419584	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	Identified in a patient with a history of sudden cardiac arrest and syncope; this variant was also identified in a relative with syncope who harbored additional cardiogenetic variants (PMID: 30129429); Reported in a patient with thoracic aortic aneurysm in published literature; however, it is unclear if additional variants were identified in this patient (PMID: 34047934); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 34047934, 30129429)
PreventionGenetics, part of Exact Sciences	RCV004544614	SCV004771688	likely benign	COL3A1-related disorder	2022-05-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).