Submissions for variant NM_005902.4(SMAD3):c.636G>A (p.Met212Ile)

gnomAD frequency: 0.00016  dbSNP: rs202094530

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238592	SCV000297195	uncertain significance	Loeys-Dietz syndrome	2015-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000654829	SCV000739669	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-04-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000654829	SCV000776730	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-01-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000654829	SCV000902147	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000654829	SCV000904464	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-09-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000842512	SCV000984535	likely benign	not provided	2020-11-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000842512	SCV003917400	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SMAD3: PP2, BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488492	SCV004241810	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: SMAD3 c.636G>A (p.Met212Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251430 control chromosomes. The observed variant frequency is approximately 65.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD3 causing Aortopathy phenotype (3.8e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.636G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003909876	SCV004720086	likely benign	SMAD3-related condition	2021-06-23	criteria provided, single submitter	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).