Submissions for variant NM_000257.4(MYH7):c.452C>T (p.Pro151Leu) (rs730880837)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158735	SCV000208670	likely pathogenic	not provided	2012-07-20	criteria provided, single submitter	clinical testing	p.Pro151Leu (CCG>CTG): c.452 C>T in exon 5 of the MYH7 gene (NM_000257.2). The Pro151Leu variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro151Leu results in a semi-conservative amino acid substitution of one non-polar residue for another at a position that is conserved across species. In silico analysis predicts Pro151Leu is probably damaging to the protein structure/function. Mutations in nearby residues (Lys146Asn, Ser148Ile, Tyr162Cys) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Pro151Leu was not observed in over 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, while Pro151Leu 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).
Center for Genetic Medicine Research,Children's National Medical Center	RCV000232512	SCV000265789	likely pathogenic	Congenital myopathy	2015-12-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000168837	SCV000272051	uncertain significance	not specified	2015-01-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro151Leu variant in MYH7 has not been previously reported in individuals with cardiomyop athy and was absent from large population studies. Proline (Pro) at position 151 is highly conserved in evolution and the change to leucine (Leu) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, the clinical significance of the p.Pro151Leu variant is uncertain but there is some suspicion for a pathogenic role.
Invitae	RCV001056271	SCV001220705	uncertain significance	Hypertrophic cardiomyopathy	2019-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 151 of the MYH7 protein (p.Pro151Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with congenital myopathy (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 181305). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV001170750	SCV001333355	uncertain significance	Cardiomyopathy	2018-10-18	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000168837	SCV000280352	uncertain significance	not specified	2014-05-13	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro151Leu (c.452C>T) in the MYH7 gene. The vairant is novel. This is a semi conservative amino acid substitution with a non polar Proline replaced with a non polar Leucine. In silico analysis predicts the amino acid change to be probably damaging. The Proline at codon 151 is conserved across species. Variants in nearby codons (p. Lys146Asn, p.Ser148Ile) have been reported in association with HCM (Stenson P et al 2003). I could not find other variants at codon 151 reported in association with disease. There is no variation at codon 151 currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of Aug 12th 2012).