NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) AND Hypertrophic cardiomyopathy

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Dec 9, 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:: RCV000475413.12

Allele description [Variation Report for NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser)]

NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser)

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.3169G>A (p.Gly1057Ser)

Other names:

NM_000257.3(MYH7):c.3169G>A; NM_000257.4(MYH7):c.3169G>A

HGVS:

NC_000014.9:g.23422256C>T
NG_007884.1:g.18406G>A
NM_000257.4:c.3169G>AMANE SELECT
NP_000248.2:p.Gly1057Ser
LRG_384t1:c.3169G>A
LRG_384:g.18406G>A
NC_000014.8:g.23891465C>T
NM_000257.2:c.3169G>A
NM_000257.3:c.3169G>A
P12883:p.Gly1057Ser
c.3169G>A

Protein change:

G1057S

Links:

UniProtKB: P12883#VAR_042821; dbSNP: rs397516179

NCBI 1000 Genomes Browser:

rs397516179

Molecular consequence:

NM_000257.4:c.3169G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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ALDH1A3 [Canis lupus dingo]
ALDH1A3 [Canis lupus dingo]
Gene ID:112653444

Gene
Protein Family Models for Protein (Select 1912581207) (11)
Protein Family Models
3D structures for Gene (Select 5583) (2)
Structure
protein kinase C eta type isoform X4 [Homo sapiens]
protein kinase C eta type isoform X4 [Homo sapiens]
gi|1370465318|ref|XP_024305430.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059494	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 24, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15358028, 16199542, 24510615, 30847666, 27532257, 31513939, 30297972, 32880476, 25741868
SCV000546183	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15358028, 27532257, 29255176, 30297972, 30847666, 31513939, 29398688, 28492532
SCV000564443	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Likely pathogenic (Dec 9, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000579537	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 9, 2017)	germline	clinical testing
SCV004844779	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15358028, 24510615, 27476098, 27532257, 30847666, 31568572, 33029862, 33495596, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	not provided	not provided	108544	not provided	clinical testing, curation
Caucasian	germline	yes	7	6	not provided	not provided	yes	clinical testing

Citations

PubMed

Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling.

Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C.

J Med Genet. 2005 Oct;42(10):e59.

PubMed [citation]

PMID:: 16199542
PMCID:: PMC1735926

Implications of Genetic Testing in Dilated Cardiomyopathy.

Verdonschot JAJ, Hazebroek MR, Krapels IPC, Henkens MTHM, Raafs A, Wang P, Merken JJ, Claes GRF, Vanhoutte EK, van den Wijngaard A, Heymans SRB, Brunner HG.

Circ Genom Precis Med. 2020 Oct;13(5):476-487. doi: 10.1161/CIRCGEN.120.003031. Epub 2020 Sep 3.

PubMed [citation]

PMID:: 32880476

See all PubMed Citations (17)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059494.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Gly1057Ser variant in MYH7 has been identified in >20 individuals with hypertrophic cardiomyopathy (HCM), including 1 individual with an additional variant in another gene that may contribute to their disease and in 2 individuals with DCM (Van Driest 2004 PMID: 15358028; Kapplinger 2014 PMID: 24510615, Walsh 2017 PMID: 27532257; Hazebroek 2018 PMID: 29540472; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In addition, this variant was classified as likely pathogenic on Feb 25, 2019 by the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar Variation ID: 42950). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3.

#	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 Invitae, SCV000546183.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1057 of the MYH7 protein (p.Gly1057Ser). This variant is present in population databases (rs397516179, gnomAD 0.002%). This missense change has been observed in individuals with MYH7-related conditions (PMID: 15358028, 27532257, 29255176, 30297972, 30847666, 31513939; Invitae). ClinVar contains an entry for this variant (Variation ID: 42950). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly1057 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 29398688), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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, SCV000564443.5

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

Description

The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 2 individuals with DCM (PS4; Van Driest 2004 PMID 15358028; Kapplinger 2014 PMID:24510615, Walsh 2017 PMID:27532257; Hazebroek 2018 PMID:24510615; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). Additionally, this variant has also been reported in 1 individual with RCM and AFib, 4 individuals with unspecified heart disease or cardiomyopathy and 1 individual with LVH, CHD and trisomy 21 (Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2, PP3.

#	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 Center for Human Genetics, University of Leuven, SCV000579537.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	7	not provided	yes	clinical testing	not provided

Description

ACMG score unknown significance

#	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		7	not provided	6	not provided

From All of Us Research Program, National Institutes of Health, SCV004844779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces glycine with serine at codon 1057 in the neck and hinge domain (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have a 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 over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27476098, 27532257, 30847666, 31568572, 33029862, 33495596, Kaam et al. 2019, doi: 10.1038/s41431-019-0404-7, ClinVar SCV000564443.5) or suspected of having hypertrophic cardiomyopathy (PMID: 24510615). This variant has been identified in 2/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		7	not provided	not provided	not provided

Last Updated: Aug 25, 2024

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