ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.3100-2A>C
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.
Likely pathogenic(1); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000257.4(MYH7):c.3100-2A>C
Variation ID: 919218 Accession: VCV000919218.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q11.2 14: 23422327 (GRCh38) [ NCBI UCSC ] 14: 23891536 (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 Jun 22, 2020 Apr 20, 2024 Feb 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000257.4:c.3100-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001407004.1:c.3100-2A>C splice acceptor NC_000014.9:g.23422327T>G NC_000014.8:g.23891536T>G NG_007884.1:g.18335A>C LRG_384:g.18335A>C - Protein change
- Other names
- -
- Canonical SPDI
- NC_000014.9:23422326:T:G
-
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), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- Links
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 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV001177235.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 15, 2023 | RCV001751309.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 19, 2022 | RCV001823754.1 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Dec 8, 2021 | RCV001875841.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 10, 2022 | RCV002320396.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 28, 2021 | RCV002483964.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Jan 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not specified
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Phosphorus, Inc.
Accession: SCV002073422.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
This splice-acceptor variant is located -2 bp away from the canonical splice-site in intron 24 out of 39 total introns of the MYH7 gene. This … (more)
This splice-acceptor variant is located -2 bp away from the canonical splice-site in intron 24 out of 39 total introns of the MYH7 gene. This variant has an entry in ClinVar (919218) NM_000257.4 (MYH7): c.3100-2A>C and has occurred in GnomAD with a total MAF of 0.0016% and highest MAF of 0.0036% in the European population. This position is conserved. In silico splicing algorithms predicted that this variant will impact splicing (dbscSNV = 0.9279, MaxEntScan = 183.565% difference) and defective splicing in the MYH7 gene has previously been associated with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 32079122, 20124440). This variant has previously been reported in an individual affected with dilated cardiomyopathy (PMID: 29517769). Further evidence is needed to establish whether this variant contributes to disease formation. It has therefore been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Oct 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
MYH7-related skeletal myopathy
Myosin storage myopathy Hypertrophic cardiomyopathy 1 Myopathy, myosin storage, autosomal recessive Congenital myopathy 4A, autosomal dominant Myosin storage myopathy Dilated cardiomyopathy 1S
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002782873.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Dec 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002185408.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change affects an acceptor splice site in intron 24 of the MYH7 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 24 of the MYH7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. This variant is present in population databases (rs759013925, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 29447731, 30847666). ClinVar contains an entry for this variant (Variation ID: 919218). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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)
|
|
Uncertain significance
(Feb 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002007727.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: … (more)
Canonical splice site variant in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 29517769, 33500567, 30847666, 29447731) (less)
|
|
Uncertain significance
(Aug 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002607790.2
First in ClinVar: Nov 29, 2022 Last updated: Jul 08, 2023 |
Comment:
The c.3100-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 23 in the MYH7 gene. This variant has … (more)
The c.3100-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 23 in the MYH7 gene. This variant has been detected in individuals from noncompaction and dilated cardiomyopathy cohorts; however, some cases had other variants in cardiac-related genes (van Waning JI et al. J. Am. Coll. Cardiol., 2018 02;71:711-722; Herkert JC et al. Genet. Med., 2018 11;20:1374-1386; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of MYH7 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(May 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001341410.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes an A to C nucleotide substitution at the -2 position of intron 24 of the MYH7 gene. Splice prediction tools suggest that … (more)
This variant causes an A to C nucleotide substitution at the -2 position of intron 24 of the MYH7 gene. Splice prediction tools suggest that this variant may disrupt RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 29517769), left ventricular non-compaction (Mazzarotto et al. 2020, DOI: 10.1101/2020.01.03.19015602), noncompaction cardiomyopathy (van Waning 2020, dissertation, Erasmus University Rotterdam), and in an individual affected with hypertrophic cardiomyopathy in compound heterozygosity with a different MYH7 pathogenic missense variant (van Velzen 2018, dissertation, Erasmus University Rotterdam). This variant has also been identified in 7/282820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain Significance
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004814411.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant causes an A to C nucleotide substitution at the -2 position of intron 24 of the MYH7 gene. Splice prediction tools suggest that … (more)
This variant causes an A to C nucleotide substitution at the -2 position of intron 24 of the MYH7 gene. Splice prediction tools suggest that this variant may disrupt RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 29517769), left ventricular non-compaction (Mazzarotto et al. 2020, DOI: 10.1101/2020.01.03.19015602), noncompaction cardiomyopathy (van Waning 2020, dissertation, Erasmus University Rotterdam), and in an individual affected with hypertrophic cardiomyopathy in compound heterozygosity with a different MYH7 pathogenic missense variant (van Velzen 2018, dissertation, Erasmus University Rotterdam). This variant has also been identified in 7/282820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 12
|
|
Likely Pathogenic
(May 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847611.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.3100-2A>C variant in MYH7 has been reported in 1 individual with non-compaction cardiomyopathy (van Waning 2018). It has also been identified in 6/129142 European … (more)
The c.3100-2A>C variant in MYH7 has been reported in 1 individual with non-compaction cardiomyopathy (van Waning 2018). It has also been identified in 6/129142 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Although heterozygous loss-of-function (LOF) variants in MYH7 are not believed to be pathogenic for dominant forms of cardiomyopathy, there is evidence that can they lead to severe and early onset disease when present in trans with a second MYH7 variant (LMM data). In summary, while the clinical significance of the c.3100-2A>C variant on its own is unclear, it meets criteria to be classified as likely pathogenic for autosomal recessive HCM. ACMG/AMP Criteria applied: PVS1, PM2. (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 |
---|---|---|---|---|
Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. | Mazzarotto F | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33500567 |
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 |
Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy. | Herkert JC | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29517769 |
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy. | van Waning JI | Journal of the American College of Cardiology | 2018 | PMID: 29447731 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs759013925 ...
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.