VCV000177846.39 - ClinVar

NM_000257.4(MYH7):c.5287G>A (p.Ala1763Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(21)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000257.4(MYH7):c.5287G>A (p.Ala1763Thr)

Variation ID: 177846 Accession: VCV000177846.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23415267 (GRCh38) [ NCBI UCSC ] 14: 23884476 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 15, 2015	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.5287G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Ala1763Thr	missense
NC_000014.9:g.23415267C>T
NC_000014.8:g.23884476C>T
NG_007884.1:g.25395G>A
LRG_384:g.25395G>A
LRG_384t1:c.5287G>A

... more HGVS ... less HGVS

Protein change

A1763T

Other names

Canonical SPDI

NC_000014.9:23415266:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00007

The Genome Aggregation Database (gnomAD) 0.00009

Links

ClinGen: CA015861 dbSNP: rs727504355 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	3654	4938
LOC126861897	-	-	-	GRCh38	-	534

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Uncertain significance (1)	criteria provided, multiple submitters, no conflicts	Feb 20, 2023	RCV000154483.16
Hypertrophic cardiomyopathy	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Jan 28, 2024	RCV000464078.20
Left ventricular noncompaction cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Dec 16, 2014	RCV000208237.8
Hypertrophic cardiomyopathy 1	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000172890.9
Dilated cardiomyopathy 1S	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000578112.8
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000724585.22
Cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV000769433.18
Myopathy, myosin storage, autosomal recessive	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000577993.8
MYH7-related skeletal myopathy	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000578027.8
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Mar 9, 2023	RCV002345494.10
Congenital myopathy with fiber type disproportion Dilated cardiomyopathy 1S Hypertrophic cardiomyopathy 1 MYH7-related skeletal myopathy Myopathy, myosin storage, autosomal recessive Myosin storage myopathy	Uncertain significance (1)	criteria provided, single submitter	Apr 18, 2022	RCV002483337.8
Myosin storage myopathy	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV003320110.8
MYH7-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 3, 2024	RCV004757140.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 05, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000229809.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYH7 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Jun 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV000900826.3 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024
Uncertain significance (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000546187.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 28492532‚ 24111713‚ 24793961‚ 25611685‚ 26468400‚ 27532257‚ 27600940‚ 28790153‚ 28807990 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1763 of the MYH7 protein (p.Ala1763Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1763 of the MYH7 protein (p.Ala1763Thr). This variant is present in population databases (rs727504355, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, dilated cardiomyopathy or sudden death (PMID: 24111713, 24793961, 25611685, 26468400, 27532257, 27600940, 28790153, 28807990). ClinVar contains an entry for this variant (Variation ID: 177846). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 16, 2014)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Left ventricular noncompaction cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000264098.2 First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016	Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1S Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679791.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (6) PubMed: 22958901‚ 24033266‚ 24111713‚ 24793961‚ 25611685‚ 27247418 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 1 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679792.1 First in ClinVar: Jun 15, 2015 Last updated: Jun 15, 2015	Publications: PubMed (6) PubMed: 22958901‚ 24033266‚ 24111713‚ 24793961‚ 25611685‚ 27247418 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myosin storage myopathy Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679794.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (6) PubMed: 22958901‚ 24033266‚ 24111713‚ 24793961‚ 25611685‚ 27247418 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYH7-related skeletal myopathy Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679793.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (6) PubMed: 22958901‚ 24033266‚ 24111713‚ 24793961‚ 25611685‚ 27247418 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myopathy, myosin storage, autosomal recessive Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679795.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (6) PubMed: 22958901‚ 24033266‚ 24111713‚ 24793961‚ 25611685‚ 27247418 Number of individuals with the variant: 1
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Center for Human Genetics, University of Leuven Accession: SCV000886838.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019
Uncertain significance (Nov 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV000223881.2 First in ClinVar: Jun 15, 2015 Last updated: May 04, 2020	Publications: PubMed (9) PubMed: 25611685‚ 24793961‚ 22958901‚ 24111713‚ 26468400‚ 28807990‚ 27532257‚ 28790153‚ 27600940 Comment: The Ala1763Thr variant has been previously reported in 4 SUD cases (Dewar LJ et al., 2017), 3 DCM cases (Broch K, et al., 2018; LMM, … (more) The Ala1763Thr variant has been previously reported in 4 SUD cases (Dewar LJ et al., 2017), 3 DCM cases (Broch K, et al., 2018; LMM, Pers. Comm.; Phosphorus inc, ClinVar SCV000679791), 1 LVNC case (Blueprint, ClinVar SCV000264098), 3 myopathy cases (Phosphorus inc, ClinVar SCV000679793-5) and 7 HCM cases (Walsh et al., 2017; Cecconi M, et al., 2016; Bos JM, et al., 2014; Berge & Leren, 2014; Invitae, ClinVar SCV000546187; Phosphorus inc, ClinVar SCV000679792). It is present at an elevated frequency of 0.0000685 in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The MYH7 Ala1736Thr variant occurs in a conserved region, and in silico tools (SIFT, PolyPhen2, MutationTaster and CADD) support a damaging role for this variant. We have identified this variant in a single HCM proband who has no family history of disease (Ingles J et al., 2017; Burns C, et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is not rare in the general population and therefore probands cannot be counted as evidence. In silico tools predict it to deleterious (PP3), therefore we classify MYH7 Ala1763Thr as a variant of 'uncertain significance'. (less)
Uncertain significance (Apr 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYH7-related skeletal myopathy Myosin storage myopathy Hypertrophic cardiomyopathy 1 Myopathy, myosin storage, autosomal recessive Congenital myopathy 4A, autosomal dominant Myosin storage myopathy Dilated cardiomyopathy 1S Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002776322.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Feb 20, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003845001.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (4) PubMed: 24111713‚ 27532257‚ 28807990‚ 31931689 Comment: Variant summary: MYH7 c.5287G>A (p.Ala1763Thr) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of … (more) Variant summary: MYH7 c.5287G>A (p.Ala1763Thr) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (6.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.5287G>A has been reported in the literature in individuals affected with HCM, DCM, or sudden unexpected death. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with a pathogenic variant has been reported (TTN c.48868C>T, p.Arg16290X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten 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. (less)
Uncertain significance (Oct 21, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003815412.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Dec 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001356062.4 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 24111713‚ 24793961‚ 25611685‚ 26468400‚ 27532257‚ 27600940‚ 28790153‚ 28807990‚ 31513939 Comment: This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction tool indicates that this variant may have deleterious impact … (more) This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction tool indicates that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 31513939, 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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. (less)
Uncertain Significance (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004814353.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (8) PubMed: 24111713‚ 24793961‚ 25611685‚ 26468400‚ 27532257‚ 27600940‚ 28790153‚ 28807990 Comment: This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces alanine with threonine at codon 1763 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 multiple individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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. (less) Number of individuals with the variant: 20
Uncertain Significance (Jun 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204153.5 First in ClinVar: Jan 31, 2015 Last updated: Apr 20, 2024	Publications: PubMed (4) PubMed: 24793961‚ 25611685‚ 24111713‚ 27532257 Comment: The p.Ala1763Thr variant in MYH7 has been reported in 1 infant with HCM, who also carried a pathogenic variant in MYBC3, and 6 individuals with … (more) The p.Ala1763Thr variant in MYH7 has been reported in 1 infant with HCM, who also carried a pathogenic variant in MYBC3, and 6 individuals with cardiomyopathy (5 with HCM, and 1 with DCM: Berge 2014, Bos 2014, Alfares 2015, Walsh 2017, LMM data). One of the individuals with HCM carried an additional pathogenic variant in MYH7 sufficient to explain their disease. This variant has also been identified in 14/126724 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504355). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1763Thr variant is uncertain. ACMG/AMP criteria applied: BS1_P. (less)
Uncertain significance (Mar 09, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002642054.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (16) PubMed: 24111713‚ 24793961‚ 25611685‚ 26468400‚ 27532257‚ 27600940‚ 28750076‚ 28790153‚ 28807990‚ 31513939‚ 31931689‚ 32894683‚ 33495597‚ 34426522‚ 34542152‚ 35653365 Comment: The p.A1763T variant (also known as c.5287G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide … (more) The p.A1763T variant (also known as c.5287G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5287. The alanine at codon 1763 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and sudden death; however, clinical details were limited (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Broch K et al. Open Heart, 2015 Oct;2:e000271; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Dewar LJ et al. Circ Cardiovasc Genet. 2017 Aug;10(4); Ramchand J et al. J Am Heart Assoc. 2020 01;9(2):e013346). In one HCM case, the individual also had a second alteration in another cardiac-related gene (Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypertrophic cardiomyopathy Affected status: yes Allele origin: unknown	Genetics and Genomics Program, Sidra Medicine Accession: SCV001434150.1 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Number of individuals with the variant: 1
Uncertain significance (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004699097.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: MYH7: PM2, PP3 Number of individuals with the variant: 1
Uncertain significance (Mar 03, 2024)	no assertion criteria provided Method: clinical testing	MYH7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005357333.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MYH7 c.5287G>A variant is predicted to result in the amino acid substitution p.Ala1763Thr. This variant was reported in multiple individuals with hypertrophic cardiomyopathy or … (more) The MYH7 c.5287G>A variant is predicted to result in the amino acid substitution p.Ala1763Thr. This variant was reported in multiple individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (Berge et al. 2014. PubMed ID: 24111713; Broch et al. 2015. PubMed ID: 26468400; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S2, Burns et al. 2017. PubMed ID: 28790153; Table S2, Robyns et al. 2020. PubMed ID: 31513939), as well as in four pediatric cases of sudden unexplained death (Dewar et al. 2017. PubMed ID: 28807990). However, another cohort study found this variant only in eight individuals in the control group and none of the hypertrophic cardiomyopathy patients (Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1763 of the MYH7 protein (p.Ala1763Thr). This variant is present in population databases (rs727504355, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, dilated cardiomyopathy or sudden death (PMID: 24111713, 24793961, 25611685, 26468400, 27532257, 27600940, 28790153, 28807990). ClinVar contains an entry for this variant (Variation ID: 177846). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The Ala1763Thr variant has been previously reported in 4 SUD cases (Dewar LJ et al., 2017), 3 DCM cases (Broch K, et al., 2018; LMM, Pers. Comm.; Phosphorus inc, ClinVar SCV000679791), 1 LVNC case (Blueprint, ClinVar SCV000264098), 3 myopathy cases (Phosphorus inc, ClinVar SCV000679793-5) and 7 HCM cases (Walsh et al., 2017; Cecconi M, et al., 2016; Bos JM, et al., 2014; Berge & Leren, 2014; Invitae, ClinVar SCV000546187; Phosphorus inc, ClinVar SCV000679792). It is present at an elevated frequency of 0.0000685 in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The MYH7 Ala1736Thr variant occurs in a conserved region, and in silico tools (SIFT, PolyPhen2, MutationTaster and CADD) support a damaging role for this variant. We have identified this variant in a single HCM proband who has no family history of disease (Ingles J et al., 2017; Burns C, et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is not rare in the general population and therefore probands cannot be counted as evidence. In silico tools predict it to deleterious (PP3), therefore we classify MYH7 Ala1763Thr as a variant of 'uncertain significance'.

Comment:

Variant summary: MYH7 c.5287G>A (p.Ala1763Thr) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (6.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.5287G>A has been reported in the literature in individuals affected with HCM, DCM, or sudden unexpected death. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with a pathogenic variant has been reported (TTN c.48868C>T, p.Arg16290X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten 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.

Comment:

This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction tool indicates that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 31513939, 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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.

Comment:

This missense variant replaces alanine with threonine at codon 1763 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 multiple individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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.

Comment:

The p.Ala1763Thr variant in MYH7 has been reported in 1 infant with HCM, who also carried a pathogenic variant in MYBC3, and 6 individuals with cardiomyopathy (5 with HCM, and 1 with DCM: Berge 2014, Bos 2014, Alfares 2015, Walsh 2017, LMM data). One of the individuals with HCM carried an additional pathogenic variant in MYH7 sufficient to explain their disease. This variant has also been identified in 14/126724 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504355). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1763Thr variant is uncertain. ACMG/AMP criteria applied: BS1_P.

Comment:

The p.A1763T variant (also known as c.5287G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5287. The alanine at codon 1763 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and sudden death; however, clinical details were limited (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Broch K et al. Open Heart, 2015 Oct;2:e000271; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Dewar LJ et al. Circ Cardiovasc Genet. 2017 Aug;10(4); Ramchand J et al. J Am Heart Assoc. 2020 01;9(2):e013346). In one HCM case, the individual also had a second alteration in another cardiac-related gene (Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

The MYH7 c.5287G>A variant is predicted to result in the amino acid substitution p.Ala1763Thr. This variant was reported in multiple individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (Berge et al. 2014. PubMed ID: 24111713; Broch et al. 2015. PubMed ID: 26468400; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S2, Burns et al. 2017. PubMed ID: 28790153; Table S2, Robyns et al. 2020. PubMed ID: 31513939), as well as in four pediatric cases of sudden unexplained death (Dewar et al. 2017. PubMed ID: 28807990). However, another cohort study found this variant only in eight individuals in the control group and none of the hypertrophic cardiomyopathy patients (Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory.	Stava TT	European journal of preventive cardiology	2022	PMID: 35653365
A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.	Park J	Human molecular genetics	2022	PMID: 34542152
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.	Harper AR	Nature genetics	2021	PMID: 33495597
Clinical Utility of a Phenotype-Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing.	Mattivi CL	Circulation. Genomic and precision medicine	2020	PMID: 32894683
Prospective Evaluation of the Utility of Whole Exome Sequencing in Dilated Cardiomyopathy.	Ramchand J	Journal of the American Heart Association	2020	PMID: 31931689
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.	Robyns T	European journal of medical genetics	2020	PMID: 31513939
Investigating the Genetic Causes of Sudden Unexpected Death in Children Through Targeted Next-Generation Sequencing Analysis.	Dewar LJ	Circulation. Cardiovascular genetics	2017	PMID: 28807990
Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing.	Burns C	Circulation. Cardiovascular genetics	2017	PMID: 28790153
Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathies.	Forleo C	PloS one	2017	PMID: 28750076
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.	Cecconi M	International journal of molecular medicine	2016	PMID: 27600940
Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.	Homburger JR	Proceedings of the National Academy of Sciences of the United States of America	2016	PMID: 27247418
Results of comprehensive diagnostic work-up in 'idiopathic' dilated cardiomyopathy.	Broch K	Open heart	2015	PMID: 26468400
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.	Bos JM	Mayo Clinic proceedings	2014	PMID: 24793961
Genetics of hypertrophic cardiomyopathy in Norway.	Berge KE	Clinical genetics	2014	PMID: 24111713
A systematic approach to assessing the clinical significance of genetic variants.	Duzkale H	Clinical genetics	2013	PMID: 24033266
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts.	Bick AG	American journal of human genetics	2012	PMID: 22958901
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYH7	-	-	-	-
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Text-mined citations for rs727504355 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.5287G>A (p.Ala1763Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs727504355 ...