VCV000043483.7 - ClinVar

NM_000432.4(MYL2):c.84A>T (p.Glu28Asp)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000432.4(MYL2):c.84A>T (p.Glu28Asp)

Variation ID: 43483 Accession: VCV000043483.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 110919113 (GRCh38) [ NCBI UCSC ] 12: 111356917 (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	Jan 31, 2015	Mar 11, 2023	Oct 5, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000432.4:c.84A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000423.2:p.Glu28Asp	missense
NC_000012.12:g.110919113T>A
NC_000012.11:g.111356917T>A
NG_007554.1:g.6465A>T
NG_065206.1:g.261T>A
LRG_393:g.6465A>T
LRG_393t1:c.84A>T	LRG_393p1:p.Glu28Asp

... more HGVS ... less HGVS

Protein change

E28D

Other names

Canonical SPDI

NC_000012.12:110919112:T:A

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.

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

Links

ClinGen: CA010541 dbSNP: rs397516410 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.
MYL2		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	504	661
LOC114827850	-	-	-	GRCh38	-	150

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	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2012	RCV000036412.5
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Oct 5, 2021	RCV003149629.2

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.	Expand all rows Collapse all rows 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 (Oct 31, 2012) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060067.6 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Comment: show Variant classified as Uncertain Significance - Favor Pathogenic. The Glu28Asp va riant in MYL2 has not been reported in the literature nor previously identified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). While this low frequency is consist ent with a disease-causing role, it is insufficient to establish this with confi dence. Glutamic acid (Glu) at position 28 is highly conserved in evolution and t he change to asparagine (Asp) was predicted to be pathogenic using a computation al tool, which was validated by our laboratory using a set of cardiomyopathy var iants with well-established clinical significance. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). This variant is m ore likely pathogenic but additional studies are needed to fully assess its clin ical significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Uncertain significance (Oct 05, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838025.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Variant classified as Uncertain Significance - Favor Pathogenic. The Glu28Asp va riant in MYL2 has not been reported in the literature nor previously identified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). While this low frequency is consist ent with a disease-causing role, it is insufficient to establish this with confi dence. Glutamic acid (Glu) at position 28 is highly conserved in evolution and t he change to asparagine (Asp) was predicted to be pathogenic using a computation al tool, which was validated by our laboratory using a set of cardiomyopathy var iants with well-established clinical significance. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). This variant is m ore likely pathogenic but additional studies are needed to fully assess its clin ical significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs397516410 ...

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 Jul 28, 2025