ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser)
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
-
NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser)
Variation ID: 42950 Accession: VCV000042950.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q11.2 14: 23422256 (GRCh38) [ NCBI UCSC ] 14: 23891465 (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 Apr 17, 2017 Feb 20, 2024 Dec 9, 2021 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000257.4:c.3169G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Gly1057Ser missense NC_000014.9:g.23422256C>T NC_000014.8:g.23891465C>T NG_007884.1:g.18406G>A LRG_384:g.18406G>A LRG_384t1:c.3169G>A P12883:p.Gly1057Ser - Protein change
- G1057S
- Other names
- NM_000257.3(MYH7):c.3169G>A
- NM_000257.4(MYH7):c.3169G>A
- Canonical SPDI
- NC_000014.9:23422255:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
---|---|---|---|---|---|---|
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 |
- | 4604 |
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. |
---|---|---|---|---|
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 29, 2017 | RCV000035843.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 5, 2023 | RCV000244617.5 | |
Likely pathogenic (3) |
reviewed by expert panel
|
Dec 9, 2021 | RCV000475413.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 7, 2023 | RCV000766440.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 5, 2023 | RCV001190251.4 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Dec 09, 2021)
|
reviewed by expert panel
Method: curation
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Cardiomyopathy Variant Curation Expert Panel
Accession: SCV000564443.5
First in ClinVar: May 29, 2016 Last updated: Dec 25, 2021 |
Comment:
The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute … (more)
The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 2 individuals with DCM (PS4; Van Driest 2004 PMID 15358028; Kapplinger 2014 PMID:24510615, Walsh 2017 PMID:27532257; Hazebroek 2018 PMID:24510615; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). Additionally, this variant has also been reported in 1 individual with RCM and AFib, 4 individuals with unspecified heart disease or cardiomyopathy and 1 individual with LVH, CHD and trisomy 21 (Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2, PP3. (less)
|
|
Likely pathogenic
(Jun 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000320054.7
First in ClinVar: Oct 02, 2016 Last updated: Jul 08, 2023 |
Comment:
The p.G1057S variant (also known as c.3169G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.G1057S variant (also known as c.3169G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide position 3169. The glycine at codon 1057 is replaced by serine, an amino acid with similar properties. This variant has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am Coll Cardiol 2004 Aug; 44(3):602-10; Kapplinger JD et al. J Cardiovasc Transl Res 2014 Apr; 7(3):347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Hazebroek MR et al. Circ Heart Fail. 2018;11:e004682; Ambry internal data). In one family with HCM, this variant was seen in two affected relatives and one unaffected relative (Robyns T et al. Eur J Hum Genet. 2017;25(12):1313-1323). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
Uncertain significance
(Feb 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, University of Leuven
Accession: SCV000579537.1
First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017 |
Comment:
ACMG score unknown significance
Number of individuals with the variant: 7
Family history: yes
Age: 47-82 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Belgium
Secondary finding: no
|
|
Uncertain significance
(Aug 29, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059494.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1057Se r variant in MYH7 has been reported in 9 individuals with HCM (Van Driest 2004, … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1057Se r variant in MYH7 has been reported in 9 individuals with HCM (Van Driest 2004, Kapplinger 2014, LMM data), but was also present in one of these individual's un affected, elderly parent. This variant has also been identified in 1/66738 Europ ean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs397516179). Glycine (Gly) at position 1057 is highly conserve d in mammals and across evolutionarily distant species and the change to serine (Ser) was predicted to be pathogenic using a computational tool clinically valid ated by our laboratory. This tool's pathogenic prediction is estimated to be cor rect 94% of the time (Jordan 2011). In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Glu1057Ser variant is un certain. (less)
Number of individuals with the variant: 5
|
|
Uncertain significance
(Nov 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502947.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Uncertain significance
(Sep 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208528.14
First in ClinVar: Feb 24, 2015 Last updated: Sep 14, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); 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: 15358028, 27532257, 24510615, 21310275, 29300372, 29540472, 31513939, 30847666, 16199542, 32894683, 32880476, 30297972, 34542152, 29255176, 31568572) (less)
|
|
Likely pathogenic
(Nov 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001357702.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with serine at codon 1057 in the neck and hinge domain (S2) domain of the MYH7 protein. Computational prediction suggests … (more)
This missense variant replaces glycine with serine at codon 1057 in the neck and hinge domain (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27476098, 27532257, 30297972, 30847666, 31568572, 33029862, 33495596; DOI:10.1038/s41431-019-0404-7) or suspected to be affected with hypertrophic cardiomyopathy (PMID: 24510615). This variant has been identified in 2/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
Pathogenic
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000546183.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1057 of the MYH7 protein (p.Gly1057Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1057 of the MYH7 protein (p.Gly1057Ser). This variant is present in population databases (rs397516179, gnomAD 0.002%). This missense change has been observed in individuals with MYH7-related conditions (PMID: 15358028, 27532257, 29255176, 30297972, 30847666, 31513939; Invitae). ClinVar contains an entry for this variant (Variation ID: 42950). 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%. This variant disrupts the p.Gly1057 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 29398688), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
Genomic Context Differs Between Human Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy. | Puckelwartz MJ | Journal of the American Heart Association | 2021 | PMID: 33764162 |
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. | Tadros R | Nature genetics | 2021 | PMID: 33495596 |
Impact of variant reclassification in the clinical setting of cardiovascular genetics. | VanDyke RE | Journal of genetic counseling | 2021 | PMID: 33029862 |
Clinical Utility of a Phenotype-Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing. | Mattivi CL | Circulation. Genomic and precision medicine | 2020 | PMID: 32894683 |
Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. | Robyns T | European journal of medical genetics | 2020 | PMID: 31513939 |
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3. | Kühnisch J | Clinical genetics | 2019 | PMID: 31568572 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). | Ho CY | Circulation | 2018 | PMID: 30297972 |
Prevalence of Pathogenic Gene Mutations and Prognosis Do Not Differ in Isolated Left Ventricular Dysfunction Compared With Dilated Cardiomyopathy. | Hazebroek MR | Circulation. Heart failure | 2018 | PMID: 29540472 |
Late Gadolinium Enhancement for Prediction of Mutation-Positive Hypertrophic Cardiomyopathy on the Basis of Panel-Wide Sequencing. | Teramoto R | Circulation journal : official journal of the Japanese Circulation Society | 2018 | PMID: 29398688 |
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 |
Repeat genetic testing with targeted capture sequencing in primary arrhythmia syndrome and cardiomyopathy. | Robyns T | European journal of human genetics : EJHG | 2017 | PMID: 29255176 |
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 |
Value of Genetic Testing for the Prediction of Long-Term Outcome in Patients With Hypertrophic Cardiomyopathy. | van Velzen HG | The American journal of cardiology | 2016 | PMID: 27476098 |
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. | Ingles J | Journal of medical genetics | 2005 | PMID: 16199542 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6a9cd1dc-183f-4897-91e7-0bfc92a4ce1b | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs397516179 ...
HelpRecord last updated Feb 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.