NM_000257.3(MYH7):c.452C>T (p.Pro151Leu) AND not specified

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 29, 2015
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000168837.2

Allele description

NM_000257.3(MYH7):c.452C>T (p.Pro151Leu)

Gene:

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.3(MYH7):c.452C>T (p.Pro151Leu)

Other names:

p.P151L:CCG>CTG

HGVS:

NC_000014.9:g.23432689G>A
NG_007884.1:g.7973C>T
NM_000257.3:c.452C>T
NP_000248.2:p.Pro151Leu
LRG_384:g.7973C>T
LRG_384p1:p.Pro151Leu
NC_000014.8:g.23901898G>A
NM_000257.2:c.452C>T

Protein change:

P151L

Links:

dbSNP: rs730880837

NCBI 1000 Genomes Browser:

rs730880837

Molecular consequence:

NM_000257.3:c.452C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000219849	CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2007)	Uncertain significance (Sep 24, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000272051	Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine)	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 29, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000280352	Stanford Center for Inherited Cardiovascular Disease,Stanford University	no assertion criteria provided	Uncertain significance (May 13, 2014)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000219849

CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2007)

Uncertain significance
(Sep 24, 2013)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000272051

Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine)

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 29, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000280352

Stanford Center for Inherited Cardiovascular Disease,Stanford University

no assertion criteria provided

Uncertain significance
(May 13, 2014)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario, SCV000219849.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

7 May 2013: This results in the substitution of a leucine for a proline at amino acid 151. This confirms the result obtained by the research laboratory. This variant has not to our knowledge been described previously. In silico analysis using Align GVGD predicted this variant to be benign. However PolyPhen, Mutation Taster and Sift all predict it to be deleterious. In addition it is highly conserved (up to chicken). Given the limited information on this variant it would be considered of unknown clinical significance or ACMG category 3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), SCV000272051.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro151Leu variant in MYH7 has not been previously reported in individuals with cardiomyopathy 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 laboratory. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Stanford Center for Inherited Cardiovascular Disease,Stanford University, SCV000280352.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Aug 16, 2018

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