NM_000257.4(MYH7):c.4909G>A (p.Ala1637Thr) AND Cardiomyopathy

Germline classification:: Likely benign (4 submissions)
Last evaluated:: Mar 22, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000758026.10

Allele description [Variation Report for NM_000257.4(MYH7):c.4909G>A (p.Ala1637Thr)]

NM_000257.4(MYH7):c.4909G>A (p.Ala1637Thr)

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.4909G>A (p.Ala1637Thr)

Other names:

p.A1637T:GCC>ACC; NM_000257.3(MYH7):c.4909G>A

HGVS:

NC_000014.9:g.23416048C>T
NG_007884.1:g.24614G>A
NM_000257.4:c.4909G>AMANE SELECT
NP_000248.2:p.Ala1637Thr
LRG_384t1:c.4909G>A
LRG_384:g.24614G>A
NC_000014.8:g.23885257C>T
NM_000257.2:c.4909G>A
NM_000257.3:c.4909G>A
NR_126491.1:n.309C>T
c.4909G>A

Protein change:

A1637T

Links:

dbSNP: rs141122361

NCBI 1000 Genomes Browser:

rs141122361

Molecular consequence:

NM_000257.4:c.4909G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_126491.1:n.309C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000564454	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Likely benign (Mar 22, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001349565	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20624503, 27574918, 25741868
SCV003838744	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Oct 19, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004814365	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20624503, 27574918, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	16	not provided	not provided	108544	not provided	clinical testing, curation

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

Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy.

Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A, Prieur F, Bresson JL, Faivre L, Eicher JC, Chassaing N, Crehalet H, Porcher R, Rodriguez-Lafrasse C, Rousson R.

Eur J Med Genet. 2010 Sep-Oct;53(5):261-7. doi: 10.1016/j.ejmg.2010.07.007. Epub 2010 Jul 30.

PubMed [citation]

PMID:: 20624503

See all PubMed Citations (4)

Details of each submission

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564454.5

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

Description

The c.4909G>A (p.Ala1637Thr) variant in MYH7 has been observed in 0.060% (FAF 95% CI; 22/24960) of African chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Additionally, computational prediction tools and conservation analysis suggest that this variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, BP4

#	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 Color Diagnostics, LLC DBA Color Health, SCV001349565.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces alanine with threonine at codon 1637 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27574918). This variant has also been identified in 25/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of 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

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV003838744.1

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

#	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 All of Us Research Program, National Institutes of Health, SCV004814365.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	16	not provided	not provided	clinical testing	PubMed (3)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		16	not provided	not provided	not provided

Last Updated: Jun 29, 2024

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