Submissions for variant NM_002474.3(MYH11):c.472G>A (p.Ala158Thr)

gnomAD frequency: 0.00034  dbSNP: rs375998236

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000247069	SCV000319325	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-26	criteria provided, single submitter	clinical testing	The p.A158T variant (also known as c.472G>A), located in coding exon 2 of the MYH11 gene, results from a G to A substitution at nucleotide position 472. The alanine at codon 158 is replaced by threonine, an amino acid with similar properties, and is located in the myosin head-like domain. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other 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.
Illumina Laboratory Services, Illumina	RCV000641579	SCV000395397	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641579	SCV000763221	likely benign	Aortic aneurysm, familial thoracic 4	2025-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000247069	SCV000905127	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 158 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 34/282866 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001355711	SCV001715141	uncertain significance	not provided	2019-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001355711	SCV001770170	likely benign	not provided	2021-04-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30122538)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000247069	SCV002042941	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-09-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282089	SCV002572230	likely benign	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.472G>A (p.Ala158Thr) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) 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 0.00012 in 251458 control chromosomes in the gnomAD database, including one homozygote. The observed variant frequency is approximately ten fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.472G>A in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224244	SCV003920238	likely benign	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2022-01-12	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in 0.2% (27/15278) of Latino alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-15823285-C-T?dataset=gnomad_r3). Tis variant is present in ClinVar, with classifications ranging from Likely Benign to Variant of Uncertain Significance (Variation ID:263862). This variant amino acid Threonine (Thr) is present in several species including the wallaby, parrot, lizard, and multiple fish, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as Likely Benign.
All of Us Research Program, National Institutes of Health	RCV000247069	SCV004816851	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 158 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 34/282866 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355711	SCV001550668	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH11  p.A158T variant was not identified in the literature but was identified in dbSNP (ID: rs375998236) and ClinVar (classified as uncertain significance by Color, Ambry Genetics, Illumina and Invitae). The variant was identified in control databases in 34 of 282866 chromosomes (1 homozygous) at a frequency of 0.0001202 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.A158 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001355711	SCV001927512	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001355711	SCV001953308	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001355711	SCV002038057	likely benign	not provided		no assertion criteria provided	clinical testing