Submissions for variant NM_002474.3(MYH11):c.2158G>A (p.Val720Ile)

gnomAD frequency: 0.00003  dbSNP: rs756408490

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001805663	SCV002053680	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 727 of the MYH11 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 reported for this variant. This variant has not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 5/282790 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.
Fulgent Genetics, Fulgent Genetics	RCV002489858	SCV002800726	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541441	SCV003471724	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 727 of the MYH11 protein (p.Val727Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs756408490, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
All of Us Research Program, National Institutes of Health	RCV001805663	SCV004823592	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 727 of the MYH11 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 reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/282790 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002541441	SCV005399848	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS). The disease mechanism for chronic intestinal pseudo-obstruction (CIPO) and familial thoracic aortic aneurysm 4 (MIM#132900) is unclear however loss of function and dominant negative have been suggested respectively. (PMID: 31944481) (I) 0108 - This gene is associated with both recessive and dominant disease. MMIHS is autosomal recessive form of disease caused by both missense variants and those resulting in a premature termination codon. Familial thoracic aortic aneurysm 4 is autosomal dominant and has been reported in patients with splice, missense and inframe deletion variants. CIPO is autosomal dominant and has only been reported in patients with protein elongation variants exclusive to isoform SM2. (PMIDs: 31389005, 31944481) (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated converter subdomain within the myosin motor domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign