Submissions for variant NM_002474.3(MYH11):c.5528C>T (p.Ser1843Leu)

gnomAD frequency: 0.00031  dbSNP: rs148621523

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704871	SCV000234825	likely benign	not provided	2021-04-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV001185497	SCV000319818	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-03-11	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027836	SCV001190456	uncertain significance	Aortic aneurysm, familial thoracic 4	2019-04-30	criteria provided, single submitter	clinical testing	MYH11 NM_002474.2 exon 39 p.Ser1843Leu (c.5528C>T): This variant has not been reported in the literature and is present in 0.06% (17/24968) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-15809106-G-A). This variant is present in ClinVar (Variation ID:201039). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV001027836	SCV001274133	uncertain significance	Aortic aneurysm, familial thoracic 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001116103	SCV001274134	uncertain significance	Lissencephaly 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001185497	SCV001351722	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-01-06	criteria provided, single submitter	clinical testing
Invitae	RCV001027836	SCV001412851	likely benign	Aortic aneurysm, familial thoracic 4	2024-02-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224199	SCV003920230	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-03-30	criteria provided, single submitter	clinical testing	MYH11 NM_002474.2 exon 39 p.Ser1843Leu (c.5528C>T): This variant has not been reported in the literature and is present in 0.06% (17/24968) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-15809106-G-A). This variant is present in ClinVar (Variation ID:201039). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003398908	SCV004120181	uncertain significance	MYH11-related condition	2022-08-18	criteria provided, single submitter	clinical testing	The MYH11 c.5549C>T variant is predicted to result in the amino acid substitution p.Ser1850Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-15809106-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.