Submissions for variant NM_002474.3(MYH11):c.3932C>T (p.Ala1311Val)

gnomAD frequency: 0.00016  dbSNP: rs185720909

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182513	SCV000234859	uncertain significance	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822715	SCV000963529	likely benign	Aortic aneurysm, familial thoracic 4	2024-12-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184502	SCV001350481	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-09-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182513	SCV002048440	uncertain significance	not provided	2021-02-14	criteria provided, single submitter	clinical testing	The MYH11 c.3932C>T; p.Ala1311Val variant (rs185720909), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 201069). This variant is found in the general population with an allele frequency of 0.012% (31/251,258 alleles) in the Genome Aggregation Database. The alanine at codon 1311 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.265). Due to limited information, the clinical significance of the p.Ala1311Val variant is uncertain at this time.
Ambry Genetics	RCV001184502	SCV002626109	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-09-14	criteria provided, single submitter	clinical testing	The c.3932C>T (p.A1311V) alteration is located in exon 29 (coding exon 28) of the MYH11 gene. This alteration results from a C to T substitution at nucleotide position 3932, causing the alanine (A) at amino acid position 1311 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330542	SCV004037760	likely benign	not specified	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.3953C>T (p.Ala1318Val) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251258 control chromosomes (gnomAD). The observed variant frequency is approximately 99 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.3953C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.