NM_000257.4(MYH7):c.29G>C (p.Gly10Ala) AND Cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 25, 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:: RCV001525375.4

Allele description [Variation Report for NM_000257.4(MYH7):c.29G>C (p.Gly10Ala)]

NM_000257.4(MYH7):c.29G>C (p.Gly10Ala)

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.29G>C (p.Gly10Ala)

Other names:

p.G10A:GGG>GCG; NM_000257.4(MYH7):c.29G>C; p.Gly10Ala

HGVS:

NC_000014.9:g.23433704C>G
NG_007884.1:g.6958G>C
NM_000257.4:c.29G>CMANE SELECT
NP_000248.2:p.Gly10Ala
LRG_384t1:c.29G>C
LRG_384:g.6958G>C
NC_000014.8:g.23902913C>G
NM_000257.2:c.29G>C
NM_000257.3:c.29G>C

Protein change:

G10A

Links:

dbSNP: rs730880826

NCBI 1000 Genomes Browser:

rs730880826

Molecular consequence:

NM_000257.4:c.29G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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GON-4-like protein isoform X3 [Homo sapiens]
GON-4-like protein isoform X3 [Homo sapiens]
gi|2462510467|ref|XP_054193200.1|

Protein
GON-4-like protein isoform X4 [Homo sapiens]
GON-4-like protein isoform X4 [Homo sapiens]
gi|2462510473|ref|XP_054193203.1|

Protein
PREDICTED: Homo sapiens gon-4 like (GON4L), transcript variant X18, mRNA
PREDICTED: Homo sapiens gon-4 like (GON4L), transcript variant X18, mRNA
gi|2462510458|ref|XM_054337221.1|

Nucleotide
Homo sapiens signal induced proliferation associated 1 like 1 (SIPA1L1), transcr...
Homo sapiens signal induced proliferation associated 1 like 1 (SIPA1L1), transcript variant 1, mRNA
gi|1677530772|ref|NM_015556.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001735453	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 31, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29555771, 25741868
SCV002041487	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Uncertain significance (Mar 25, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001735453

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 31, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002041487

ClinGen Cardiomyopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)

Uncertain significance
(Mar 25, 2021)

germline

curation

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	curation, clinical testing

Citations

PubMed

Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.

Perkins BA, Caskey CT, Brar P, Dec E, Karow DS, Kahn AM, Hou YC, Shah N, Boeldt D, Coughlin E, Hands G, Lavrenko V, Yu J, Procko A, Appis J, Dale AM, Guo L, Jönsson TJ, Wittmann BM, Bartha I, Ramakrishnan S, Bernal A, et al.

Proc Natl Acad Sci U S A. 2018 Apr 3;115(14):3686-3691. doi: 10.1073/pnas.1706096114. Epub 2018 Mar 19.

PubMed [citation]

PMID:: 29555771
PMCID:: PMC5889622

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001735453.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glycine with alanine at codon 10 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with abnormal cardiovascular phenotypes who participated in a screening study for age-related chronic disease risk among active, symptom-free adults (PMID: 29555771). This variant has been identified in 6/251230 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.

#	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 ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV002041487.1

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

Description

The NM_000257.4(MYH7):c.29G>C (p.Gly10Ala) variant has been reported in the homozygous state in 1 infant with a complex cardiac presentation that included DCM and HCM (GeneDx pers. comm.) ; however, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.002% (FAF 95% CI; 5/113546) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2.

#	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: May 7, 2024

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