NM_000257.4(MYH7):c.4717G>A (p.Glu1573Lys) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 17, 2022
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:: RCV000454653.7

Allele description [Variation Report for NM_000257.4(MYH7):c.4717G>A (p.Glu1573Lys)]

NM_000257.4(MYH7):c.4717G>A (p.Glu1573Lys)

Genes:

LOC126861897:BRD4-independent group 4 enhancer GRCh37_chr14:23884455-23885654 [Gene]
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
MHRT:myosin heavy chain associated RNA transcript [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.4717G>A (p.Glu1573Lys)

HGVS:

NC_000014.9:g.23416240C>T
NG_007884.1:g.24422G>A
NM_000257.4:c.4717G>AMANE SELECT
NP_000248.2:p.Glu1573Lys
LRG_384t1:c.4717G>A
LRG_384:g.24422G>A
NC_000014.8:g.23885449C>T
NM_000257.2:c.4717G>A
NM_000257.3:c.4717G>A
NR_126491.1:n.501C>T
P12883:p.Glu1573Lys

Protein change:

E1573K

Links:

UniProtKB: P12883#VAR_073884; dbSNP: rs750987717

NCBI 1000 Genomes Browser:

rs750987717

Molecular consequence:

NM_000257.4:c.4717G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_126491.1:n.501C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000539836	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jul 26, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002600535	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 17, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25163546, 28798025, 32880476, 21127202, 26150528 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000539836

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jul 26, 2016)

germline

clinical testing

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

SCV002600535

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 17, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Atlas of the clinical genetics of human dilated cardiomyopathy.

Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, Feng Z, Müller S, Kayvanpour E, Vogel B, Sedaghat-Hamedani F, Lim WK, Zhao X, Fradkin D, Köhler D, Fischer S, Franke J, Marquart S, Barb I, Li DT, Amr A, Ehlermann P, et al.

Eur Heart J. 2015 May 7;36(18):1123-35a. doi: 10.1093/eurheartj/ehu301. Epub 2014 Aug 27.

PubMed [citation]

PMID:: 25163546

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000539836.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with ebstein anomaly and mild hypertrabeculation of the apex, but also identified in her father with normal echo; ClinVar: VUS for first degree atrioventricular block

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600535.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: MYH7 c.4717G>A (p.Glu1573Lys) results in a conservative amino acid change in the encoded protein sequence within the Myosin tail (IPR002928). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251370 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Cardiomyopathy (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.4717G>A has been reported in the literature in individuals affected with Cardiomyopathy, Left ventricular hypertrabeculation, and Ebstein's anomaly (Jamka_2017, Verdonschot_2020, Postma_2011, Haas_2015). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with another pathogenic variant has been reported (MYH7 c.2167C>T, p.Arg723Gly, internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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