Submissions for variant NM_002474.3(MYH11):c.3233T>C (p.Ile1078Thr)

gnomAD frequency: 0.00001  dbSNP: rs193922629

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030296	SCV000052963	uncertain significance	not specified	2019-05-30	criteria provided, single submitter	clinical testing	MYH11 c.3254T>C (p.Ile1085Thr, NM_001040113.1) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3254T>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002313723	SCV000739225	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-08-19	criteria provided, single submitter	clinical testing	The p.I1078T variant (also known as c.3233T>C), located in coding exon 24 of the MYH11 gene, results from a T to C substitution at nucleotide position 3233. The isoleucine at codon 1078 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641574	SCV000763216	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 1085 of the MYH11 protein (p.Ile1085Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). 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: 36618). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
GeneDx	RCV001753433	SCV002007461	uncertain significance	not provided	2019-10-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Fulgent Genetics, Fulgent Genetics	RCV002496467	SCV002813381	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002313723	SCV004817811	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1085 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/251308 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.