VCV000044473.47 - ClinVar

NM_002471.4(MYH6):c.2928+5G>A

Germline

Classification

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.

(16)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002471.4(MYH6):c.2928+5G>A

Variation ID: 44473 Accession: VCV000044473.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23393661 (GRCh38) [ NCBI UCSC ] 14: 23862870 (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	Dec 6, 2016	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002471.4:c.2928+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000014.9:g.23393661C>T
NC_000014.8:g.23862870C>T
NG_023444.1:g.19617G>A
LRG_389:g.19617G>A
LRG_389t1:c.2928+5G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000014.9:23393660:C:T

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.

0.00020 (T)

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

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00167

The Genome Aggregation Database (gnomAD) 0.00172

Exome Aggregation Consortium (ExAC) 0.00176

The Genome Aggregation Database (gnomAD), exomes 0.00180

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00185

Links

ClinGen: CA134301 dbSNP: rs28730772 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.
MYH6		-	-	GRCh38 GRCh37	1898	2417

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.
Hypertrophic cardiomyopathy 14	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 30, 2024	RCV000230824.12
not specified	Likely benign (4)	criteria provided, single submitter	Apr 28, 2015	RCV000037464.22
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jul 19, 2018	RCV000248019.4
Atrial septal defect 3	Benign (1)	criteria provided, single submitter	Aug 1, 2017	RCV000577962.1
Dilated cardiomyopathy 1EE	Benign (1)	criteria provided, single submitter	Aug 1, 2017	RCV000578015.1
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000590639.22
Cardiomyopathy	Benign (1)	criteria provided, single submitter	Jun 24, 2020	RCV000770448.3

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 (Feb 29, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697924.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 23396983‚ 24503780 Comment: Variant summary: The c.2928+5G>A variant affects a conserved intronic nucleotide. One in-silico tool predicts damaging outcome for this variant. 4/5 programs in Alamut predict that … (more) Variant summary: The c.2928+5G>A variant affects a conserved intronic nucleotide. One in-silico tool predicts damaging outcome for this variant. 4/5 programs in Alamut predict that this variant does not significantly affect normal splicing. This variant is found in 214/121412 control chromosomes at a frequency of 0.0017626, which exceeds the predicted maximal expected frequency of a pathogenic allele (0.000025), suggesting this variant is benign. This variant has been reported in DCM and HCM patients, including one patient who also carries a TTN c.39069T>A/p.Tyr13023X (classified likely pathogenic in ClinVar). In addition, one clinical laboratory classified this variant as likely benign. Taken together, this variant was classified as benign. (less)
Likely benign (Oct 22, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000527900.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 23396983, 26656175, 32277046)
Likely benign (Jul 19, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318283.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 26656175 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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)
Likely benign (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy 14 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287401.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Benign (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1EE Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679870.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (1) PubMed: 24033266 Number of individuals with the variant: 1
Benign (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atrial septal defect 3 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679869.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (1) PubMed: 24033266 Number of individuals with the variant: 1
Benign (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 14 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679871.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (1) PubMed: 24033266 Number of individuals with the variant: 1
Benign (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004033283.11 First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024	Comment: MYH6: BP4, BS1, BS2 Number of individuals with the variant: 6
Likely benign (Apr 28, 2015)	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: SCV000061122.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Comment: c.2829+5G>A in intron 22 of MYH6: This variant is not expected to have clinical significance because it has been identified in 0.3% (190/66740) European chromos … (more) c.2829+5G>A in intron 22 of MYH6: This variant is not expected to have clinical significance because it has been identified in 0.3% (190/66740) European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28730772). (less) Number of individuals with the variant: 10
Benign (Jun 24, 2020)	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 Study: Canadian Open Genetics Repository Accession: SCV000901891.2 First in ClinVar: May 06, 2019 Last updated: Jan 01, 2022
Likely benign (Oct 26, 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: SCV001157740.4 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001927804.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV001969665.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743333.3 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	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: SCV001957637.1 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: SCV001923214.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

Variant summary: The c.2928+5G>A variant affects a conserved intronic nucleotide. One in-silico tool predicts damaging outcome for this variant. 4/5 programs in Alamut predict that this variant does not significantly affect normal splicing. This variant is found in 214/121412 control chromosomes at a frequency of 0.0017626, which exceeds the predicted maximal expected frequency of a pathogenic allele (0.000025), suggesting this variant is benign. This variant has been reported in DCM and HCM patients, including one patient who also carries a TTN c.39069T>A/p.Tyr13023X (classified likely pathogenic in ClinVar). In addition, one clinical laboratory classified this variant as likely benign. Taken together, this variant was classified as benign.

Comment:

This alteration is classified as likely 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.

Comment:

c.2829+5G>A in intron 22 of MYH6: This variant is not expected to have clinical significance because it has been identified in 0.3% (190/66740) European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28730772).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.	Bottillo I	Gene	2016	PMID: 26656175
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.	Pugh TJ	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24503780
A systematic approach to assessing the clinical significance of genetic variants.	Duzkale H	Clinical genetics	2013	PMID: 24033266
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983

Text-mined citations for rs28730772 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_002471.4(MYH6):c.2928+5G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28730772 ...