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

dbSNP: rs730880837

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158735	SCV000208670	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018); Reported in association of LVNC in published literatutre ( (PMIDs 33500567; 27854218); This variant is associated with the following publications: (PMID: 27854218, 27532257, 29300372, 33500567)
Laboratory for Molecular Medicine, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056271	SCV001220705	uncertain significance	Hypertrophic cardiomyopathy	2023-04-13	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 181305). This missense change has been observed in individual(s) with congenital myopathy and/or left ventricular noncompaction (PMID: 27854218, 33500567). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 151 of the MYH7 protein (p.Pro151Leu). 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	2020-11-09	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001265605	SCV001443680	uncertain significance	See cases	2020-11-17	criteria provided, single submitter	clinical testing	We observed the c.452C>T (p.P151L) genetic variant in a 22-y.o. proband diagnosed with left ventricular non-compaction and heart rhythm disorders. To our knowledge, the p.P151L variant was absent in large population studies. According to the online in silico analysis (PolyPhen2, SIFT, MutationTaster), the p.P151L variant is probably pathogenic. In the absence of family screening and functional studies we can only classify the p.P151L genetic variant as the variant on uncertain clinical significance.
Ambry Genetics	RCV002336363	SCV002635215	uncertain significance	Cardiovascular phenotype	2023-02-15	criteria provided, single submitter	clinical testing	The p.P151L variant (also known as c.452C>T), located in coding exon 3 of the MYH7 gene, results from a C to T substitution at nucleotide position 452. The proline at codon 151 is replaced by leucine, an amino acid with similar properties. This alteration was identified in an individual with congenital myopathy; however additional information was not provided (Punetha J et al. J Neuromuscul Dis, 2016 05;3:209-225). This alteration has also been reported in a left ventricular non-compaction (LVNC) cohort (Mazzarotto F et al. Genet Med, 2021 May;23:856-864). 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.
Revvity Omics, Revvity	RCV000158735	SCV003815400	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
Center for Genetic Medicine Research, Children's National Medical Center	RCV000232512	SCV000265789	likely pathogenic	Congenital myopathy	2015-12-01	flagged submission	research
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).