Submissions for variant NM_000258.2(MYL3):c.92G>A (p.Arg31His) (rs199639940)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000221537	SCV000272078	uncertain significance	not specified	2015-01-19	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg31His vari ant in MYL3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (13/8764) of East Asian chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1996399 40) and 1/427 healthy controls from one study (Kapplinger 2014). Arginine (Arg) at position 31 is not conserved in mammals or in evolutionarily distant species and 1 mammal species (manatee) carries a histidine (His) at this position, raisi ng the possibility that this change may be tolerated. In summary, while the clin ical significance of the p.Arg31His variant is uncertain, its presence in genera l population and lack of evolutionarily conservation suggest that it is more lik ely to be benign.
Invitae	RCV000629148	SCV000750064	likely benign	Hypertrophic cardiomyopathy	2017-11-04	criteria provided, single submitter	clinical testing
Color	RCV000771967	SCV000904921	uncertain significance	Cardiomyopathy	2018-05-29	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the N-terminal proline-rich region of the MYL3 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Arginine at this codon is poorly conserved in mammals. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy, who also carried a pathogenic variant in the TNNI3 gene (PMID: 26199943). This variant has been identified in 21/18870 East Asian chromosomes (0.11%) by the Genome Aggregation Database (gnomAD). Poor evolutionary conservation and relatively high frequency in the general population suggest this variant may not be disease-causing. However, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego	RCV000852967	SCV000995716	likely benign	Amyloidogenic transthyretin amyloidosis	2019-05-20	criteria provided, single submitter	clinical testing

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