Submissions for variant NM_000257.4(MYH7):c.5410G>A (p.Ala1804Thr)

dbSNP: rs730880818

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158701	SCV000208636	pathogenic	not provided	2012-12-10	criteria provided, single submitter	clinical testing	p.Ala1804Thr (GCC>ACC): c.5410 G>A in exon 37 of the MYH7 gene (NM_000257.2). The Ala1804Thr variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala1804Thr results in a non-conservative amino acid substitution of a non-polar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ala1804Thr is probably damaging to the protein structure/function. Mutations in nearby residues (Gln1794Glu, Glu1801Gly, Gly1808Ala) have been reported in association with DCM, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ala1804Thr was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Ala1804Thr is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s).
Ambry Genetics	RCV002345539	SCV002650513	uncertain significance	Cardiovascular phenotype	2021-05-14	criteria provided, single submitter	clinical testing	The p.A1804T variant (also known as c.5410G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5410. The alanine at codon 1804 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an individual reported to have dilated cardiomyopathy; however, details were limited (Forleo C et al. PLoS One, 2017 Jul;12:e0181842). 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.
Invitae	RCV002515075	SCV003442251	uncertain significance	Hypertrophic cardiomyopathy	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1804 of the MYH7 protein (p.Ala1804Thr). This variant is present in population databases (rs730880818, gnomAD 0.0009%). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 28750076, 35653365). ClinVar contains an entry for this variant (Variation ID: 181280). 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 expected to disrupt MYH7 protein function with a positive 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.