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NM_000257.4(MYH7):c.1405G>A (p.Asp469Asn) AND Cardiomyopathy

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Dec 1, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001798499.4

Allele description [Variation Report for NM_000257.4(MYH7):c.1405G>A (p.Asp469Asn)]

NM_000257.4(MYH7):c.1405G>A (p.Asp469Asn)

Gene:
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q11.2
Genomic location:
Preferred name:
NM_000257.4(MYH7):c.1405G>A (p.Asp469Asn)
HGVS:
  • NC_000014.9:g.23428957C>T
  • NG_007884.1:g.11705G>A
  • NM_000257.4:c.1405G>AMANE SELECT
  • NP_000248.2:p.Asp469Asn
  • LRG_384t1:c.1405G>A
  • LRG_384:g.11705G>A
  • NC_000014.8:g.23898166C>T
  • NM_000257.2:c.1405G>A
  • NM_000257.3:c.1405G>A
Protein change:
D469N
Links:
dbSNP: rs397516106
NCBI 1000 Genomes Browser:
rs397516106
Molecular consequence:
  • NM_000257.4:c.1405G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Cardiomyopathy (CMYO)
Synonyms:
Cardiomyopathies
Identifiers:
MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002042251CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 8, 2021) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004822808All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 1, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.

Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, Olivotto I, Bustamante CD, Dewey FE, Ho CY, Spudich JA, Ashley EA.

Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6701-6. doi: 10.1073/pnas.1606950113. Epub 2016 May 31.

PubMed [citation]
PMID:
27247418
PMCID:
PMC4914177

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]
PMID:
27532257
PMCID:
PMC5116235
See all PubMed Citations (6)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV002042251.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004822808.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (6)

Description

This missense variant replaces aspartic acid with asparagine at codon 469 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with affected with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 33495596, 33495597), and in one individual affected with an unspecified cardiomyopathy (PMID: 33764162). This variant has been identified in 4/282848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: Sep 29, 2024