NM_000257.4(MYH7):c.2707G>A (p.Glu903Lys) AND Hypertrophic cardiomyopathy 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 24, 2024
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:: RCV003313941.2

Allele description [Variation Report for NM_000257.4(MYH7):c.2707G>A (p.Glu903Lys)]

NM_000257.4(MYH7):c.2707G>A (p.Glu903Lys)

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.2707G>A (p.Glu903Lys)

HGVS:

NC_000014.9:g.23424122C>T
NG_007884.1:g.16540G>A
NM_000257.4:c.2707G>AMANE SELECT
NP_000248.2:p.Glu903Lys
LRG_384t1:c.2707G>A
LRG_384:g.16540G>A
NC_000014.8:g.23893331C>T
NM_000257.2:c.2707G>A
NM_000257.3:c.2707G>A

Protein change:

E903K

Links:

dbSNP: rs730880756

NCBI 1000 Genomes Browser:

rs730880756

Molecular consequence:

NM_000257.4:c.2707G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy 1
Synonyms:: Familial hypertrophic cardiomyopathy 1; MYH7-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0008647; MedGen: C3495498; OMIM: 192600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004013808	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 29300372, 25524337, 18403758, 15358028, 25741868
SCV005061761	Regional Center For Medical Genetics Timis, Louis Turcanu Emergency Hospital for Children Timisoara	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004013808

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

unknown

clinical testing

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

SCV005061761

Regional Center For Medical Genetics Timis, Louis Turcanu Emergency Hospital for Children Timisoara

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 24, 2024)

germline

research

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
Romanian	germline	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, Jongbloed JDH, Macaya D, Manrai A, Orland K, Richard G, Spoonamore K, Thomas M, Thomson K, Vincent LM, Walsh R, Watkins H, Whiffin N, et al.

Genet Med. 2018 Mar;20(3):351-359. doi: 10.1038/gim.2017.218. Epub 2018 Jan 4.

PubMed [citation]

PMID:: 29300372
PMCID:: PMC5876064

Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.

Coppini R, Ho CY, Ashley E, Day S, Ferrantini C, Girolami F, Tomberli B, Bardi S, Torricelli F, Cecchi F, Mugelli A, Poggesi C, Tardiff J, Olivotto I.

J Am Coll Cardiol. 2014 Dec 23;64(24):2589-2600. doi: 10.1016/j.jacc.2014.09.059.

PubMed [citation]

PMID:: 25524337
PMCID:: PMC4270453

See all PubMed Citations (5)

Details of each submission

From 3billion, SCV004013808.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29300372. Predicted Consequence/Location:). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYH7 related disorder (PMID: 15358028). Different missense changes at the same codon (p.Glu903Gln, p.Glu903Gly) have been reported to be associated with MYH7 related disorder (PMID: 18403758, 25524337). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Regional Center For Medical Genetics Timis, Louis Turcanu Emergency Hospital for Children Timisoara, SCV005061761.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Romanian	not provided	not provided	not provided	research	PubMed (1)

Description

The variant is not present in healthy population databases (gnomAD v4.1.0, genomes and exomes). In silico predictions supports the pathogenicity of the variant (REVEL score = 0.88 > 0.75). Other P/LP variants are reported in the literature in Hypertrophic cardiomyopathy for the same amino acid residue. The variant was previously described in patients with hypertrophic cardiomyopathy (PMID: 15358028). Therefore the variant was classified as likely pathogenic, according to ACMG 2015 guidelines.

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

Last Updated: Sep 29, 2024

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