ClinVar Miner

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

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Total submissions: 6
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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).

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