Submissions for variant NM_000257.4(MYH7):c.5120T>C (p.Ile1707Thr)

gnomAD frequency: 0.00001  dbSNP: rs730880811

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158683	SCV000208618	uncertain significance	not provided	2012-06-25	criteria provided, single submitter	clinical testing	p.Ile1707Thr (ATT>ACT): c.5120 T>C in exon 35 of the MYH7 gene (NM_000257.2). The Ile1707Thr variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ile1707Thr results in a non-conservative amino acid substitution of a non-polar Isoleucine with a polar Threonine at a position that is conserved in mammals. The NHLBI ESP Exome Variant Server reports Ile1707Thr was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In addition, mutations in nearby codons (Leu1706Pro, Arg1712Gln, Arg1712Trp) have been reported in association with myopathy and HCM, supporting the functional importance of this region of the protein. However, in silico analysis predicts Ile1707Thr likely has a benign effect on the protein structure/function.In summary, the clinical significance of the Ile1707Thr variant in the MYH7 gene is currently unknown. The variant is found in HCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001186243	SCV001352616	uncertain significance	Cardiomyopathy	2022-11-25	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1707 of the MYH7 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 been reported in two individuals affected with sudden unexpected death (PMID: 26272908, 26383259). This variant has not been identified 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	RCV002336360	SCV002644687	uncertain significance	Cardiovascular phenotype	2022-01-04	criteria provided, single submitter	clinical testing	The p.I1707T variant (also known as c.5120T>C), located in coding exon 33 of the MYH7 gene, results from a T to C substitution at nucleotide position 5120. The isoleucine at codon 1707 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in sudden unexplained death cohorts with limited clinical details (Santori M et al. Arch Dis Child, 2015 Oct;100:952-6; Hertz CL et al. Int J Legal Med, 2016 Jan;130:91-102). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.