Submissions for variant NM_000257.4(MYH7):c.4283T>C (p.Leu1428Ser)

gnomAD frequency: 0.00006  dbSNP: rs727503244

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000473362	SCV001842660	uncertain significance	Hypertrophic cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.4283T>C (p.Leu1428Ser) variant in MYH7 has been reported in at least 2 individuals with HCM (Alfares 2015 PMID:25611685; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; LMM per. comm.), but has also been identified in 0.0053% (FAF 95% CI, 12/129150) of non-Finnish European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151240	SCV000199117	uncertain significance	not specified	2016-12-15	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu1428Se r variant in MYH7 has been identified in at least 3 individuals with HCM (Ho 201 0, Homburger 2016, Murphy 2016, LMM data). This variant has also been identified in 4/67704 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs727503244). Leucine (Leu) at position 14 28 is highly conserved in mammals and across evolutionarily distant species and the change to serine (Ser) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction i s estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Leu 1428Ser variant is uncertain.
GeneDx	RCV001701529	SCV000208587	uncertain significance	not provided	2022-09-14	criteria provided, single submitter	clinical testing	Reported in association with hypertrophic cardiomyopathy (Ho et al., 2010; Alfares et al., 2015; Homburger et al., 2016; Murphy et al., 2016; Walsh et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 26914223, 27532257, 27224906, 20818890, 25611685, 34542152, 28606303)
Blueprint Genetics	RCV000208499	SCV000264091	likely pathogenic	Restrictive cardiomyopathy	2015-11-23	criteria provided, single submitter	clinical testing
Invitae	RCV000473362	SCV000546197	uncertain significance	Hypertrophic cardiomyopathy	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1428 of the MYH7 protein (p.Leu1428Ser). This variant is present in population databases (rs727503244, gnomAD 0.009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20818890, 25611685, 26914223, 27224906, 27247418). ClinVar contains an entry for this variant (Variation ID: 164289). 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.
Ambry Genetics	RCV000618508	SCV000737035	uncertain significance	Cardiovascular phenotype	2022-10-14	criteria provided, single submitter	clinical testing	The p.L1428S variant (also known as c.4283T>C), located in coding exon 29 of the MYH7 gene, results from a T to C substitution at nucleotide position 4283. The leucine at codon 1428 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in a few hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Ho CY et al. N. Engl. J. Med. 2010;363:552-63; Alfares AA et al. Genet. Med. 2015;17:880-8; Murphy SL et al. J Cardiovasc Transl Res. 2016;9:153-61). This amino acid position is highly conserved in available vertebrate species. 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.
Color Diagnostics, LLC DBA Color Health	RCV000777946	SCV000914044	uncertain significance	Cardiomyopathy	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 1428 of the MYH7 protein. Computational prediction suggests that this variant may have 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 been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 20818890, 26914223, 27532257, 33495597). This variant has been identified in 12/282834 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.
AiLife Diagnostics, AiLife Diagnostics	RCV001701529	SCV002503363	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505151	SCV002816637	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-11-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001701529	SCV003817693	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777946	SCV003838101	uncertain significance	Cardiomyopathy	2022-01-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701529	SCV001929716	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701529	SCV001970485	uncertain significance	not provided		no assertion criteria provided	clinical testing
Cohesion Phenomics	RCV000473362	SCV003803028	benign	Hypertrophic cardiomyopathy	2022-10-10	no assertion criteria provided	clinical testing