VCV000042828.28 - ClinVar

NM_000257.4(MYH7):c.1180G>A (p.Asp394Asn)

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.

(4)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000257.4(MYH7):c.1180G>A (p.Asp394Asn)

Variation ID: 42828 Accession: VCV000042828.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23429306 (GRCh38) [ NCBI UCSC ] 14: 23898515 (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	Dec 22, 2024	Aug 1, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.1180G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Asp394Asn	missense
NC_000014.9:g.23429306C>T
NC_000014.8:g.23898515C>T
NG_007884.1:g.11356G>A
LRG_384:g.11356G>A
LRG_384t1:c.1180G>A

... more HGVS ... less HGVS

Protein change

D394N

Other names

Canonical SPDI

NC_000014.9:23429305: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.

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

Links

ClinGen: CA010330 dbSNP: rs397516093 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.
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	3715	5026

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	Aug 13, 2014	RCV000035704.6
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 27, 2022	RCV000700699.6
not provided	Likely pathogenic (1)	criteria provided, single submitter	Aug 1, 2022	RCV002292459.16
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Feb 19, 2019	RCV000769461.4

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.
Uncertain significance (Jun 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000829466.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28492532‚ 27532257‚ 23233322‚ 33500567 Comment: This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants … (more) This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. This variant disrupts the p.Asp394 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23233322, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 42828). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 33500567). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 394 of the MYH7 protein (p.Asp394Asn). (less)
Uncertain significance (Aug 13, 2014)	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: SCV000059355.6 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Comment: The Asp394Asn variant in MYH7 has been identified by our laboratory in 1 Caucasi an child with infant-onset LVNC and DCM and 1 neonate of … (more) The Asp394Asn variant in MYH7 has been identified by our laboratory in 1 Caucasi an child with infant-onset LVNC and DCM and 1 neonate of unspecified ancestry wi th LVNC. This variant was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the Asp394Asn variant is uncert ain. (less) Number of individuals with the variant: 2
Uncertain significance (Feb 19, 2019)	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 Accession: SCV000900855.2 First in ClinVar: May 06, 2019 Last updated: May 31, 2020
Likely pathogenic (Aug 01, 2022)	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: SCV002585460.16 First in ClinVar: Oct 22, 2022 Last updated: Dec 22, 2024	Comment: MYH7: PM2, PM5, PP2, PP3, PP4, PS4:Supporting Number of individuals with the variant: 1

Comment:

This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. This variant disrupts the p.Asp394 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23233322, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 42828). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 33500567). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 394 of the MYH7 protein (p.Asp394Asn).

Comment:

The Asp394Asn variant in MYH7 has been identified by our laboratory in 1 Caucasi an child with infant-onset LVNC and DCM and 1 neonate of unspecified ancestry wi th LVNC. This variant was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the Asp394Asn variant is uncert ain.

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
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
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
Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program.	Kassem HSh	Journal of cardiovascular translational research	2013	PMID: 23233322

Text-mined citations for rs397516093 ...

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 Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.1180G>A (p.Asp394Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516093 ...