Submissions for variant NM_002474.3(MYH11):c.4016G>A (p.Arg1339His)

gnomAD frequency: 0.00002  dbSNP: rs374271463

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182515	SCV000234861	uncertain significance	not provided	2021-03-19	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 has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 201071; Landrum et al., 2016)
Illumina Laboratory Services, Illumina	RCV000699160	SCV000395285	uncertain significance	Aortic aneurysm, familial thoracic 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000288562	SCV000395286	uncertain significance	Lissencephaly, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699160	SCV000827858	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1346 of the MYH11 protein (p.Arg1346His). This variant is present in population databases (rs374271463, gnomAD 0.005%). 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: 201071). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000699160	SCV000896506	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121346	SCV001279940	uncertain significance	Lissencephaly 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.
Color Diagnostics, LLC DBA Color Health	RCV001192184	SCV001360185	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1346 of the MYH11 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 8/282358 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.
Ambry Genetics	RCV001192184	SCV002621149	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-07-08	criteria provided, single submitter	clinical testing	The p.R1339H variant (also known as c.4016G>A), located in coding exon 29 of the MYH11 gene, results from a G to A substitution at nucleotide position 4016. The arginine at codon 1339 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000699160	SCV005398132	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS). The disease mechanism for chronic intestinal pseudo-obstruction (CIPO) and familial thoracic aortic aneurysm 4 (MIM#132900) is unclear however loss of function and dominant negative have been suggested respectively. (PMID: 31944481) (I) 0108 - This gene is associated with both recessive and dominant disease. MMIHS is autosomal recessive form of disease caused by both missense variants and those resulting in a premature termination codon. Familial thoracic aortic aneurysm 4 is autosomal dominant and has been reported in patients with splice, missense and inframe deletion variants. CIPO is autosomal dominant and has only been reported in patients with protein elongation variants exclusive to isoform SM2 (PMIDs: 31389005, 31944481). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin tail 1 domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. Two alternative amino acid changes at the same position (p.(Arg1339Ser), p.(Arg1339Cys)) have been reported as uncertain significance in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as uncertain significance in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign