Submissions for variant NM_002474.3(MYH11):c.1749+4C>G

gnomAD frequency: 0.00015  dbSNP: rs776271431

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251770	SCV000319266	uncertain significance	Cardiovascular phenotype	2014-04-07	criteria provided, single submitter	clinical testing	The c.1749+4C>G intronic variant results from a C to G substitution 4 nucleotides after coding exon 13 in the MYH11 gene. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. Based on nucleotide sequence alignment, this position is not well conserved in available vertebrate species. The BDGP splice site prediction tool predicts a weakening in the native splice donor site efficiency, whereas the ESEfinder splice site prediction tool predicts a slight strengthening in the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537087	SCV000641002	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the MYH11 gene. It does not directly change the encoded amino acid sequence of the MYH11 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs776271431, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 263833). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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	RCV001179394	SCV001344048	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-02	criteria provided, single submitter	clinical testing	This variant causes a C to G nucleotide substitution at the +4 position of intron 15 of the MYH11 gene. Splice site prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. 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 10/282468 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	RCV002494787	SCV002812884	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-09-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155137	SCV003844493	uncertain significance	not specified	2023-02-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001179394	SCV004824766	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-08-06	criteria provided, single submitter	clinical testing	This variant causes a C to G nucleotide substitution at the +4 position of intron 15 of the MYH11 gene. Splice site prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. 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 10/282468 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.
PreventionGenetics, part of Exact Sciences	RCV003930026	SCV004738678	likely benign	MYH11-related disorder	2022-03-09	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).