VCV000043092.53 - ClinVar

NM_000257.4(MYH7):c.597A>G (p.Ala199=)

Germline

Top reviewed classifications are shown here.

Submission summary:

25 submissions

21 submitters

10 conditions

Reviewed by expert panel

Benign

Dec 2016 by ClinGen Cardio… FDA Recognized Database

for Cardiomyopathy

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000257.4(MYH7):c.597A>G (p.Ala199=)

Variation ID: 43092 Accession: VCV000043092.53

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23431803 (GRCh38) [ NCBI UCSC ] 14: 23901012 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jul 18, 2015	Sep 29, 2024	Dec 15, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.597A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Ala199=	synonymous
NC_000014.9:g.23431803T>C
NC_000014.8:g.23901012T>C
NG_007884.1:g.8859A>G
LRG_384:g.8859A>G
LRG_384t1:c.597A>G

... more HGVS ... less HGVS

Protein change

Other names

NM_000257.3(MYH7):c.597A>G

Canonical SPDI

NC_000014.9:23431802:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00579 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00609

The Genome Aggregation Database (gnomAD) 0.00853

Trans-Omics for Precision Medicine (TOPMed) 0.00961

Exome Aggregation Consortium (ExAC) 0.01092

1000 Genomes Project 0.00579

The Genome Aggregation Database (gnomAD), exomes 0.01026

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01076

Links

ClinGen: CA016520 dbSNP: rs2069541 VarSome

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
Gene	OMIM	HI score Help 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.
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	3643	4925

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.
not specified	Benign (9)	criteria provided, multiple submitters, no conflicts	Sep 24, 2019	RCV000035987.37
Hypertrophic cardiomyopathy	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000228969.23
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jun 29, 2015	RCV000244941.12
MYH7-related skeletal myopathy	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000331196.14
Dilated Cardiomyopathy, Dominant	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000385660.14
Left ventricular noncompaction cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000388895.14
Cardiomyopathy	Benign (4)	reviewed by expert panel	Dec 15, 2016	RCV000758048.16
Hypertrophic cardiomyopathy 1	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV001094074.13
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Oct 13, 2023	RCV001705656.17
Myosin storage myopathy	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV003320091.8

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.
Benign (Dec 15, 2016)	reviewed by expert panel (ClinGen CMP ACMG Specifications v1) Method: curation	Cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Cardiomyopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000564502.5 First in ClinVar: Oct 02, 2016 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 29300372 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2c987756-3504-454e-b234-61113cfe99e8 Comment: The filtering allele frequency of the c.597A>G (p.Ala199=) variant in the MYH7 gene is 1.44% (1013/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), … (more) The filtering allele frequency of the c.597A>G (p.Ala199=) variant in the MYH7 gene is 1.44% (1013/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). (less)
Benign (Feb 10, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000151927.2 First in ClinVar: May 17, 2014 Last updated: Jul 18, 2015
Benign (Sep 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV001433057.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020
Benign (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000902623.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (May 02, 2010)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059639.6 First in ClinVar: May 03, 2013 Last updated: Mar 04, 2019	Comment: The Ala199Ala silent variant is not expected to have clinical significance becau se it does not alter an amino acid residue and is not located … (more) The Ala199Ala silent variant is not expected to have clinical significance becau se it does not alter an amino acid residue and is not located near a splice junc tion. In addition, it is present in 1-3% of the general population (dbSNP rs2069 541). (less) Number of individuals with the variant: 135
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001856390.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (Nov 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239493.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Benign (Oct 13, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001477598.3 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004822682.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 2745
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005296908.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303253.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Dilated Cardiomyopathy, Dominant Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000386316.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Left Ventricular Noncompaction Cardiomyopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000386313.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Myosin storage myopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000386314.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypertrophic cardiomyopathy 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000386311.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	MYH7-related skeletal myopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000386315.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Oct 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic Cardiomyopathy Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003803027.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000284289.9 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Benign (Jun 29, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318838.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932605.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958246.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918422.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035641.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741529.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967656.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

The filtering allele frequency of the c.597A>G (p.Ala199=) variant in the MYH7 gene is 1.44% (1013/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372).

Comment:

The Ala199Ala silent variant is not expected to have clinical significance becau se it does not alter an amino acid residue and is not located near a splice junc tion. In addition, it is present in 1-3% of the general population (dbSNP rs2069 541).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2c987756-3504-454e-b234-61113cfe99e8	-	-	-	-

Text-mined citations for rs2069541 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.597A>G (p.Ala199=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2069541 ...