Submissions for variant NM_002474.3(MYH11):c.3291C>T (p.Ala1097=)

gnomAD frequency: 0.00016  dbSNP: rs147605116

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182504	SCV000234850	likely benign	not provided	2023-03-19	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV000249544	SCV000319397	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2015-02-02	criteria provided, single submitter	clinical testing	The c.3312C>T variant (also known as p.A1104A), located in coding exon 25, results from a C to T substitution at nucleotide position 3312 of the MYH11 gene. This nucleotide substitution does not change the amino acid at codon 1104. However, this change occurs in the third to last base pair of coding exon 25, which gives it potentialto have some effect on normal mRNA splicing.Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable.This variant was previously reported in the SNPDatabase as rs147605116. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.03% (4/12,994) of total alleles studied and 0.05% (4/8,600) ofEuropean American alleles. This nucleotide position is well conserved in available vertebrate species, but the T allele is present in African clawed frog. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV000249544	SCV000395357	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617637	SCV000739199	uncertain significance	Cardiovascular phenotype	2019-08-12	criteria provided, single submitter	clinical testing	The c.3291C>T variant (also known as p.A1097A), located in coding exon 24 of the MYH11 gene, results from a C to T substitution at nucleotide position 3291. This nucleotide substitution does not change the amino acid at codon 1097. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001089156	SCV000763250	likely benign	Aortic aneurysm, familial thoracic 4	2025-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000249544	SCV001360073	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193406	SCV001362198	likely benign	not specified	2019-07-22	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.3312C>T (p.Ala1104Ala) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.6e-05 in 250420 control chromosomes (gnomAD). The observed variant frequency is approximately 77 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3312C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x likely benign and 4x uncertain significance). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182504	SCV001715139	uncertain significance	not provided	2020-06-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000249544	SCV004239414	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-07	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583183	SCV000692245	uncertain significance	Marfan syndrome	2017-04-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947544	SCV004774739	likely benign	MYH11-related disorder	2023-09-05	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).