ClinVar Genomic variation as it relates to human health
NM_002471.4(MYH6):c.292G>A (p.Glu98Lys)
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.
Uncertain significance(9); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002471.4(MYH6):c.292G>A (p.Glu98Lys)
Variation ID: 44474 Accession: VCV000044474.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23405680 (GRCh38) [ NCBI UCSC ] 14: 23874889 (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 May 12, 2024 Dec 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002471.4:c.292G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002462.2:p.Glu98Lys missense NC_000014.9:g.23405680C>T NC_000014.8:g.23874889C>T NG_023444.1:g.7598G>A NG_065207.1:g.1213C>T LRG_389:g.7598G>A LRG_389t1:c.292G>A LRG_389p1:p.Glu98Lys - Protein change
- E98K
- Other names
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- Canonical SPDI
- NC_000014.9:23405679:C:T
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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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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00030
Trans-Omics for Precision Medicine (TOPMed) 0.00032
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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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LOC114827851 | - | - | - | GRCh38 | - | 242 |
MYH6 | - | - |
GRCh38 GRCh37 |
1828 | 2331 |
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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Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 8, 2023 | RCV000037465.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 17, 2023 | RCV000252583.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 25, 2023 | RCV000467043.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 9, 2017 | RCV000770460.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765154.3 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jun 20, 2023 | RCV000761867.25 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 10, 2019 | RCV001256736.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 2, 2022 | RCV002470732.2 |
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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Likely benign
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934831.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: MYH6 c.292G>A (p.Glu98Lys) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. … (more)
Variant summary: MYH6 c.292G>A (p.Glu98Lys) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251480 control chromosomes (gnomAD), predominantly at a frequency of 0.00047 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eleven ClinVar submitters have assessed the variant since 2014: ten have classified the variant as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Hypertrophic cardiomyopathy 14 Dilated cardiomyopathy 1EE Atrial septal defect 3 Sick sinus syndrome 3, susceptibility to
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896383.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jun 15, 2020)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503388.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Uncertain significance
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Atrial septal defect 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767251.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however gain of function is suggested (PMID: 20656787). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however this is only in individuals with atrial septal defect (PMID: 22194935). (I) 0115 - Variants in this gene are known to have variable expressivity, however this is only in individuals with atrial septal defect (PMID: 22194935). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (71 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated motor head domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as likely benign, but more commonly as a VUS in individuals with hypertrophic cardiomyopathy or sudden unexplained death who often had additional VUSs in related genes (ClinVar, LOVD, PMID: 28797094, PMID: 28771489, PMID: 31376648). Additionally, it has been reported in a homozygous individual with Shone complex, mitrial atresia, double outlet right ventricle and coarctation of the aorta (PMID: 28991257), and within a control cohort (PMID: 25163546). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Mar 17, 2023)
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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: SCV000318221.8
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The p.E98K variant (also known as c.292G>A), located in coding exon 2 of the MYH6 gene, results from a G to A substitution at nucleotide … (more)
The p.E98K variant (also known as c.292G>A), located in coding exon 2 of the MYH6 gene, results from a G to A substitution at nucleotide position 292. The glutamic acid at codon 98 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), sudden unexplained death and congenital heart disease (Granados-Riveron JT et al. Hum. Mol. Genet., 2010 Oct;19:4007-16; Lopes LR et al. Heart, 2015 Feb;101:294-301; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Mendes de Almeida R et al. PLoS ONE, 2017 Aug;12:e0182946; Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601 ;Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212; Theis JL et al. Circ Genom Precis Med, 2021 Feb;14:e003126). 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. (less)
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Uncertain significance
(Feb 09, 2017)
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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
Study: Canadian Open Genetics Repository
Accession: SCV000901903.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Likely benign
(Oct 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061123.6
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 3
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Uncertain significance
(Dec 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433142.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Uncertain significance
(Jun 20, 2023)
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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: SCV001782806.4
First in ClinVar: Aug 14, 2021 Last updated: Jul 22, 2023 |
Comment:
Reported in individuals with cardiomyopathy (HCM and DCM) or congenital heart defects, though also present in at least one control individual (Granados-Riveron et al., 2010; … (more)
Reported in individuals with cardiomyopathy (HCM and DCM) or congenital heart defects, though also present in at least one control individual (Granados-Riveron et al., 2010; Haas et al., 2015; Lopes et al., 2015; Jin et al., 2017; Mademont-Soler et al., 2017; Mendes de Almeida et al., 2017; Theis et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28771489, 20656787, 25351510, 28991257, 25163546, 33325730, 28797094, 37194601, 22194935, 35621855, 31376648) (less)
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Uncertain significance
(Dec 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 14
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000546165.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 98 of the MYH6 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 98 of the MYH6 protein (p.Glu98Lys). This variant is present in population databases (rs140596256, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or congenital heart disease (PMID: 20656787, 25351510, 28771489, 28797094, 28991257). ClinVar contains an entry for this variant (Variation ID: 44474). 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 MYH6 protein function with a positive predictive value of 80%. 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. (less)
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Uncertain significance
(Aug 01, 2018)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892081.23
First in ClinVar: Mar 31, 2019 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Sep 22, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924864.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
Given that this variant has not segregated with disease (a congenital heart defect) in a family and its high minor allele frequency in population databases, … (more)
Given that this variant has not segregated with disease (a congenital heart defect) in a family and its high minor allele frequency in population databases, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is weak case data. This variant has been seen in at least 3 cases of complex heart defect and an individual with obstructive HCM plus Wolff-Parkinson-White syndrome. The variant did not segregate in a family with a complex heart defect. It was also present in controls. This variant is present in ClinVar. It has been reported by 3 labs, all of which classify it as a variant of uncertain significance. This variant has been reported by Illumina Clinical Services Laboratory. Ambry has seen this variant in one individual. The Laboratory for Molecular Medicine has seen this variant in 2 individuals from 2 families: in 1 adult with obstructive HCM with WPW, and in 1 child with a complex heart defect (an affected relative was negative). Therefore this variant did not segregate with the congenital heart defect. This variant has been reported in Granados-Riveron et al 2010 in both their cohort of patients with congenital heart defects as well as controls. According to the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0")." The glutamic acid at codon 98 is conserved across species, as are neighboring amino acids. This variant is present in 58 out of 123,129 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, this variant is present in 48 out of 55,853 individuals of European (non-Finnish descent), 4 out of 7,652 individuals of African descent (highest MAF=0.026%), 3 out of 16,791 individuals of Latino descent, 2 out of 8,624 individuals of East Asian descent and 1 out of 15,391 individuals of South Asian descent. This variant is present in a population of 480 controls (Granados-Riveron et al 2010), although it is not clear how many had this variant. The supplementary data is not available for review. (less)
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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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Genetic Association Between Hypoplastic Left Heart Syndrome and Cardiomyopathies. | Theis JL | Circulation. Genomic and precision medicine | 2021 | PMID: 33325730 |
Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug-induced arrhythmia and sudden unexplained deaths. | Martinez-Matilla M | Forensic science international. Genetics | 2019 | PMID: 31376648 |
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. | Jin SC | Nature genetics | 2017 | PMID: 28991257 |
Whole gene sequencing identifies deep-intronic variants with potential functional impact in patients with hypertrophic cardiomyopathy. | Mendes de Almeida R | PloS one | 2017 | PMID: 28797094 |
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy. | Mademont-Soler I | PloS one | 2017 | PMID: 28771489 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Atlas of the clinical genetics of human dilated cardiomyopathy. | Haas J | European heart journal | 2015 | PMID: 25163546 |
Cardiac alpha-myosin (MYH6) is the predominant sarcomeric disease gene for familial atrial septal defects. | Posch MG | PloS one | 2011 | PMID: 22194935 |
Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects. | Granados-Riveron JT | Human molecular genetics | 2010 | PMID: 20656787 |
Text-mined citations for rs140596256 ...
HelpRecord last updated May 12, 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.