ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)
Variation ID: 14097 Accession: VCV000014097.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23424107 (GRCh38) [ NCBI UCSC ] 14: 23893316 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Apr 20, 2024 Dec 15, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2722C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Leu908Val missense NC_000014.9:g.23424107G>C NC_000014.8:g.23893316G>C NG_007884.1:g.16555C>G LRG_384:g.16555C>G LRG_384t1:c.2722C>G LRG_384p1:p.Leu908Val P12883:p.Leu908Val - Protein change
- L908V
- Other names
- p.L908V:CTG>GTG
- NM_000257.3(MYH7):c.2722C>G
- Canonical SPDI
- NC_000014.9:23424106:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MYH7 | No evidence available | No evidence available |
GRCh38 GRCh37 |
3578 | 4827 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Mar 10, 2017 | RCV000015153.40 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 12, 2021 | RCV000035820.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 17, 2022 | RCV000078452.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV000247943.11 | |
Pathogenic (4) |
reviewed by expert panel
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Dec 15, 2016 | RCV000458449.24 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2023 | RCV001177579.16 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 15, 2016)
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reviewed by expert panel
Method: curation
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Cardiomyopathy Variant Curation Expert Panel
Accession: SCV000564438.5
First in ClinVar: Feb 26, 2016 Last updated: Dec 11, 2022 |
Comment:
The c.2722C>G (p.Leu908Val) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1638703; PMID:8483915 PMID:12473556; PMID:12975413; PMID:27532257; Partners LMM ClinVar SCV000059471.5; … (more)
The c.2722C>G (p.Leu908Val) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1638703; PMID:8483915 PMID:12473556; PMID:12975413; PMID:27532257; Partners LMM ClinVar SCV000059471.5; AGCMC Sydney ClinVar SCV000692499.1; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:1638703; PMID:8483915; Partners LMM ClinVar SCV000059471.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PP3 (less)
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Pathogenic
(Nov 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264086.2
First in ClinVar: Feb 26, 2016 Last updated: Mar 04, 2019 |
Number of individuals with the variant: 2
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Pathogenic
(Sep 16, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331349.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Jul 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917841.2
First in ClinVar: Jun 03, 2019 Last updated: Aug 07, 2021 |
Comment:
Variant summary: MYH7 c.2722C>G (p.Leu908Val) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four … (more)
Variant summary: MYH7 c.2722C>G (p.Leu908Val) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251552 control chromosomes. c.2722C>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Epstein_1992, VanDriest_2002, Morita_2008, Alpert_2005, Alpert_2005, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The rate of translocation of acting filaments as measured by in-vitro motility assays was 35% of wild-type levels (Cuda_1993). Subsequently, a gain of function effect was observed as an increase in actin filament velocity in the in-vitro motility assay (Palmiter_2000) and an increase in actin sliding velocity (Alpert_2005). Multiple clinical diagnostic laboratories and an expert panel (ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000319946.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.L908V pathogenic mutation (also known as c.2722C>G), located in coding exon 21 of the MYH7 gene, results from a C to G substitution at … (more)
The p.L908V pathogenic mutation (also known as c.2722C>G), located in coding exon 21 of the MYH7 gene, results from a C to G substitution at nucleotide position 2722. The leucine at codon 908 is replaced by valine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in families with hypertrophic cardiomyopathy (HCM) and strongly segregated with disease, though incomplete penetrance and a low incidence of sudden death were noted (Epstein ND et al. Circulation. 1992;86(2):345-52; al-Mahdawi S et al. Br Heart J. 1993;69(2):136-41; Woo A et al. Heart. 2003;89(10):1179-85). This alteration has also been reported in additional HCM cohorts (Lopes LR et al. Heart. 2015;101(4):294-301; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A.. 2016;113(24):6701-6; Walsh R et al. Genet. Med. 2017 02;19(2):192-203). In vitro motility assays showed an increase in actin filament velocities and gain of function (Palmiter KA et al. J Muscle Res Cell Motil. 2000;21(7):609-20; Alpert NR et al. Am J Physiol Heart Circ Physiol. 2005;288(3):H1097-102). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000208505.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple unrelated individuals with HCM referred for genetic testing at GeneDx and in the published literature (Epstein et al., 1992; Atiga et al., … (more)
Reported in multiple unrelated individuals with HCM referred for genetic testing at GeneDx and in the published literature (Epstein et al., 1992; Atiga et al., 2000; Van Driest et al., 2002; Woo et al., 2003; Alpert et al., 2005; Morita et al., 2008; Rodriguez et al., 2011; Pan et al., 2012; Kapplinger et al., 2014; Murphy et al., 2016; Marian et al., 2018; Mattivi et al., 2020; Burstein et al., 2021; Hathaway et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated L908V increases the velocity of actin filament movement in the in vitro motility assays performed using cardiac or skeletal muscle tissue from L908V heterozygous individuals (Palmiter et al., 2000; Alpert et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9172070, 20560001, 26914223, 8514894, 21642240, 11227787, 10615387, 7731997, 12881443, 23074333, 12473556, 15858117, 18480046, 21310275, 12428185, 9475582, 12975413, 15358028, 24510615, 12820698, 8435239, 1638703, 8483915, 15528230, 28166811, 27532257, 25351510, 27247418, 28606303, 18403758, 29300372, 10725281, 31324451, 31447099, 29540445, 33673806, 32746448, 31006259, 34135346, 32894683, 31996208, 8281650, 31905684, 22555271, 21135372) (less)
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Pathogenic
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042654.3
First in ClinVar: Jan 03, 2022 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001341816.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces leucine with valine at codon 908 in the neck and hinge domain of the MYH7 protein. Computational prediction suggests that this … (more)
This missense variant replaces leucine with valine at codon 908 in the neck and hinge domain 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). An in vitro motility assay has shown that the mutant protein exhibits enhanced mechanical performance at the single molecule level (PMID: 11227787). This variant has been reported in numerous individuals affected with hypertrophic cardiomyopathy (PMID: 15528230, 1638703, 8435239, 8483915, 10725281, 12473556, 15858117, 18403758, 24510615, 25351510, 26914223, 27247418, 27532257). This variant has been shown to segregate with hypertrophic cardiomyopathy in studies of two large families with 50-60% penetrance in adults and mild prognosis (PMID: 15528230, 1638703). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Apr 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004844781.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces leucine with valine at codon 908 in the neck and hinge domain of the MYH7 protein. Computational prediction suggests that this … (more)
This missense variant replaces leucine with valine at codon 908 in the neck and hinge domain 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). An in vitro motility assay has shown that the mutant protein exhibits enhanced mechanical performance at the single molecule level (PMID: 11227787). This variant has been reported in numerous individuals affected with hypertrophic cardiomyopathy (PMID: 15528230, 1638703, 8435239, 8483915, 10725281, 12473556, 15858117, 18403758, 24510615, 25351510, 26914223, 27247418, 27532257). This variant has been shown to segregate with hypertrophic cardiomyopathy in studies of two large families with 50-60% penetrance in adults and mild prognosis (PMID: 15528230, 1638703). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059471.6
First in ClinVar: May 03, 2013 Last updated: Aug 14, 2019 |
Comment:
The p.Leu908Val variant in MYH7 has been well established as pathogenic for HCM. It has been reported in many families with HCM and segregated with … (more)
The p.Leu908Val variant in MYH7 has been well established as pathogenic for HCM. It has been reported in many families with HCM and segregated with disease in > 50 affected relatives (Epstein 1992, al-Mahdawi 1993, Cuda 1993, Rayment 1995, W oo 2003, Van Driest 2002, Fananapazir 1993, Alpert 2005, Van Driest 2004). In ad dition, studies have shown that this variant may impact protein function (Cuda 1 993, Alpert 2005). This variant has been identified in 1/14560 European chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org /; dbSNP rs121913631). In summary, the p.Leu908Val variant meets criteria to be classified as pathogenic for autosomal dominant HCM based upon recurrence in aff ected individuals, segregation studies, extremely low frequency in the general p opulation and functional evidence. ACMG/AMP Criteria: PS4, PP1_Strong; PS3_Suppo rting; PM2; PP3. (less)
Number of individuals with the variant: 46
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Pathogenic
(Mar 10, 2017)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000692499.2
First in ClinVar: Feb 15, 2018 Last updated: Dec 11, 2022 |
Comment:
The MYH7 Leu908Val variant has been reported in more than 15 HCM probands (see literature), and in particular has been found to cosegregate with disease … (more)
The MYH7 Leu908Val variant has been reported in more than 15 HCM probands (see literature), and in particular has been found to cosegregate with disease in a few large families (Alpert NR, et al., 2005; Woo A, et al., 2003; Epstein ND, et al., 1992). In vitro assays suggest that the variant may impact myosin cross-bridge kinetics (Palmiter et al., 2000) and increase the velocity by which myosin translocated actin (Alpert NR, et al., 2005). The variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the 1000 genomes project (http://www.1000genomes.org/). We identified this variant in an HCM proband with a family history of disease, however segregation studies were not possible. Computational tools SIFT, PolyPhen-2, MutationTaster predict that this variant is deleterious. In summary, based on the large amount of probands reported with this variant, the strong segregation data, in vitro assays indicative of a functional effect, rarity in the general population and in silico tools predicting a deletrious effect, we classify the MYH7 Leu908Val variant "pathogenic". (less)
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Pathogenic
(Dec 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000546238.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 908 of the MYH7 protein (p.Leu908Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 908 of the MYH7 protein (p.Leu908Val). This variant is present in population databases (rs121913631, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 1638703, 8483915, 10725281, 12473556, 12975413, 15358028, 15858117, 18403758, 21642240; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14097). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 8483915, 9172070, 11227787, 15528230). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 1993)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035410.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2016 |
Comment on evidence:
Fananapazir et al. (1993) found evidence, on soleus muscle biopsy, of central core disease (117000) in 10 of 13 hypertrophic cardiomyopathy (CMH1; 192600) patients with … (more)
Fananapazir et al. (1993) found evidence, on soleus muscle biopsy, of central core disease (117000) in 10 of 13 hypertrophic cardiomyopathy (CMH1; 192600) patients with the leu908-to-val mutation. Although the mutations in the MYH7 gene were associated with skeletal muscle changes characteristic of central core disease, such was not found in patients with hypertrophic cardiomyopathy unlinked to MYH7. Notably, in 1 branch of a family with the L908V mutation, 2 adults and 3 children had histologic changes of central core disease without evidence of cardiac hypertrophy by echocardiogram. One of the adults had skeletal myopathic changes. McKenna (1993), who stated that he had never seen clinical evidence of skeletal myopathy in patients with CMH1, doubted the significance of the findings. (less)
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Pathogenic
(Oct 03, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280334.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
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 … (more)
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. GBased on the strong case data, segregation data, and absence in large population samples, we consider it very likely disease causing. Per ClinVar, both LMM (SCV000059471) and Emory (SCV000110306) consider it pathogenic. This variant has been reported in at least 18 unrelated cases of HCM (including the cases in our center). There is very strong segregation data in 3 families and good functional data available. We have seen this variant in two unrelated patients with HCM in our center. Epstein et al. (1992) reported this variant in a very large kindred with very strong segregation data: Leu908Val was present in all 19 affected members of the family, who spanned 3 generations [Fananapazir et al. (1993) appears to discuss this same family.] Van Driest et al. (2002) identified it in 3 unrelated HCM patients at the Mayo Clinic. The same group later reported 8 HCM patients with this variant from their cohort; presumably 3 of these cases are redundant (Bost et al 2014). Van Driest et al. (2004) reported it in 4 unrelated patients, but it’s unclear if these include the 3 from 2002. al-Mahdawi et al. (1993) identified it in one HCM family. Mohiddin et al. (2003) found it in two unrelated HCM cases. Woo et al. (2003) found it in 3 separate families. In one family it segregated with disease in 8 family members from 3 generations (some of them 4th degree relatives). Alpert et al. (2005) found Leu908Val in a family that also carried an Asp906Gly variant in trans—the result of two brothers in one HCM family marrying two sisters in another HCM family. Among family members with only the Leu908Val variant, it segregated with disease in 21 family members. Two individuals with both mutations developed severe HCM. Yu et al. (2005) found it in an Australian family. Morita et al. (2008 + supplemental data) found it in three unrelated HCM cases. Variation at nearby codons of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Ala901Gly, Glu903Lys (Van Driest et al. 2004), Cys905Phe and Asp906Gly (Harvard Sarcomere Protein Gene Mutation Database). I could find no other variants at the same codon (ClinVar, Bos et al 2014 (Mayo cohort of >1000 cases, dbSNP; as of 8 Oct 2014). Mutationtaster predicts it to be disease causing and PolyPhen2 predicts it to be possibly damaging. There is functional data available: Cuda et al. (1993, 1997) took skeletal muscle biopsies from HCM patients with this variant, and showed that the mutant cardiac myosin is also present in skeletal muscle and has abnormal function in an in vitro assay in which actin filaments are translocated by myosin bound to a coverslip surface. Fananapazir et al. (1993) analyzed skeletal muscle biopsies from HCM patients, and found 10 of 13 patients with the L908V mutation to have a myopathy resembling central core disease: a non-progressive skeletal myopathy characterized by loss of mitochondria. Palmiter et al. (2000) found the variant to alter the kinetics of the myosin cross-bridge cycle. Alpert et al. (2005) found Leu908Val to increase the velocity of actin translocation by myosin (isolated from HCM patient muscle biopsies) in vitro. This is a conservative amino acid change from a nonpolar Leucine to a nonpolar Valine. The Leucine at codon 908 is completely conserved across 44 vertebrate species examined. Surrounding residues are also highly conserved. This variant is in the rod domain of the beta-myosin heavy chain protein (Rayment et al. 1995) localized to the coiled-coil alpha-helical S-2 region (Cuda et al. 1997). In total the Leu908Val variant has not been seen in ~7341 published controls and publicly available population datasets. No variation at codon 908 is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian African American individuals (as of 1/15/2012). It was not observed in 841 published controls: Epstein et al. (1992) did not observe the variant in 50 controls. Van Driest et al. (2002) did not report controls. al-Mahdawi et al. (1993) did not find it in 5 controls. Mohiddin et al. (2003) did not find it in 200 controls. Woo et al. (2003) did not find it in 106 controls. Van Driest et al. (2004) did not observe the variant in 100 Caucasian and 100 African American controls (likely redundant with Bos et al 2014). Yu et al. (2005) did not find it in 100 Australian controls matched for ethnicity. Morita et al. (2008) did not find it in 180 ethnicity-matched controls. The Leu908Val variant is present in dbSNP as rs121913631 (“probable-pathogenic”). It was submitted by the OMIM staff at Johns Hopkins. (less)
Number of individuals with the variant: 18
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel. | Kelly MA | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29300372 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation. | Homburger JR | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 27247418 |
Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. | Murphy SL | Journal of cardiovascular translational research | 2016 | PMID: 26914223 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy. | Rodriguez G | Circulation. Cardiovascular genetics | 2011 | PMID: 21642240 |
Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease. | Yu B | Journal of clinical pathology | 2005 | PMID: 15858117 |
Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations. | Alpert NR | American journal of physiology. Heart and circulatory physiology | 2005 | PMID: 15528230 |
Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15358028 |
Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis. | Woo A | Heart (British Cardiac Society) | 2003 | PMID: 12975413 |
Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. | Van Driest SL | Circulation | 2002 | PMID: 12473556 |
R403Q and L908V mutant beta-cardiac myosin from patients with familial hypertrophic cardiomyopathy exhibit enhanced mechanical performance at the single molecule level. | Palmiter KA | Journal of muscle research and cell motility | 2000 | PMID: 11227787 |
Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations. | Atiga WL | Circulation | 2000 | PMID: 10725281 |
The in vitro motility activity of beta-cardiac myosin depends on the nature of the beta-myosin heavy chain gene mutation in hypertrophic cardiomyopathy. | Cuda G | Journal of muscle research and cell motility | 1997 | PMID: 9172070 |
Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. | Rayment I | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7731997 |
Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations. | Fananapazir L | Circulation | 1994 | PMID: 8281650 |
Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy. | Cuda G | The Journal of clinical investigation | 1993 | PMID: 8514894 |
Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. | Fananapazir L | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8483915 |
Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy. | al-Mahdawi S | British heart journal | 1993 | PMID: 8435239 |
Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the beta-myosin heavy chain gene. A 908Leu----Val mutation and a 403Arg----Gln mutation. | Epstein ND | Circulation | 1992 | PMID: 1638703 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYH7 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/bd7ac89f-9ef0-4c1b-9884-893fd733703d | - | - | - | - |
McKenna, W. J. Personal Communication. 1993. London, England | - | - | - | - |
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Text-mined citations for rs121913631 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.