VCV000177629.32 - ClinVar

NM_000257.4(MYH7):c.5326A>G (p.Ser1776Gly)

Interpretation:: Uncertain significance
Review status:: reviewed by expert panel FDA Recognized Database
Submissions:: 16
First in ClinVar:: Jan 31, 2015
Most recent Submission:: Jun 24, 2023
Last evaluated:: Dec 15, 2016
Accession:: VCV000177629.32
Variation ID:: 177629
Description:: single nucleotide variant

NM_000257.4(MYH7):c.5326A>G (p.Ser1776Gly)

Allele ID

175442

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

14q11.2

Genomic location

14: 23415228 (GRCh38) GRCh38 UCSC

14: 23884437 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.5326A>G MANE Select	NP_000248.2:p.Ser1776Gly	missense
NC_000014.9:g.23415228T>C
NC_000014.8:g.23884437T>C
NG_007884.1:g.25434A>G
LRG_384:g.25434A>G
LRG_384t1:c.5326A>G
	P12883:p.Ser1776Gly

... more HGVS ... less HGVS

Protein change

S1776G

Other names

NM_000257.3(MYH7):c.5326A>G

Canonical SPDI

NC_000014.9:23415227:T:C

Functional consequence

Global minor allele frequency (GMAF)

Allele frequency

The Genome Aggregation Database (gnomAD), exomes 0.00003

The Genome Aggregation Database (gnomAD) 0.00006

The Genome Aggregation Database (gnomAD) 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00005

Links

ClinGen: CA015944

UniProtKB: P12883#VAR_020821

dbSNP: rs369437262

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
not specified	Uncertain significance	3	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV000154209.8
Primary familial hypertrophic cardiomyopathy	Uncertain significance	1	criteria provided, single submitter	May 18, 2016	RCV000168915.5
Hypertrophic cardiomyopathy	Uncertain significance	3	reviewed by expert panel	Dec 15, 2016	RCV000462813.10
not provided	Uncertain significance	4	criteria provided, multiple submitters, no conflicts	Jan 31, 2022	RCV000514376.6
Cardiovascular phenotype	Uncertain significance	1	criteria provided, single submitter	Oct 31, 2022	RCV000620185.4
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	Oct 7, 2021	RCV000765157.3
Cardiomyopathy	Uncertain significance	2	criteria provided, multiple submitters, no conflicts	May 25, 2022	RCV001170485.8
Hypertrophic cardiomyopathy 1	Uncertain significance	1	criteria provided, single submitter	Jul 16, 2021	RCV002265629.1

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	3025	4107

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Uncertain significance (Dec 15, 2016)	reviewed by expert panel (ClinGen CMP ACMG Specifications v1) Method: curation	- Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Cardiomyopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000564457.5 First in ClinVar: Jan 31, 2015 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 29300372 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5d9a840f-4e17-4378-a41d-341cf6eab7b8 Comment: The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID: … (more) The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID: 30297972) but has also been identified in 0.02% (2/8654) of East Asian chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). 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 uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3 (less)
Uncertain significance (Apr 19, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000609658.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Uncertain significance (May 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Primary familial hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000740371.1 First in ClinVar: Jan 26, 2017 Last updated: Jan 26, 2017
Uncertain significance (Nov 29, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	- not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000203861.4 First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018	Publications: PubMed (11) PubMed: 11861413‚ 16918501‚ 21239446‚ 11861410‚ 15136674‚ 27247418‚ 29300372‚ 28518168‚ 27532257‚ 29121657‚ 30297972 Comment: The p.Ser1776Gly variant in MYH7 has been identified in at least 12 individuals with HCM (Blair 2002, Fokstuen 2010, Homburger 2016, Walsh 2017, Kelly 2018, … (more) The p.Ser1776Gly variant in MYH7 has been identified in at least 12 individuals with HCM (Blair 2002, Fokstuen 2010, Homburger 2016, Walsh 2017, Kelly 2018, Ho 2018, LMM data) and segregated with disease in 1 affected family member (Blair 2 002). It has also been identified in 0.03% (6/19954) of East Asian and 0.02% (5/ 24968) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Comp utational prediction tools and conservation analysis suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. Moreover, this variant was classified as a variant of uncert ain significance on December 15, 2016 by the ClinGen-approved Inherited Cardiomy opathy expert panel (SCV000564457.2). In summary, the clinical significance of t he p.Ser1776Gly variant is uncertain due to conflicting evidence. ACMG/AMP Crite ria applied: PP3. (less) Number of individuals with the variant: 8
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: SCV001434151.1 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Number of individuals with the variant: 1
Uncertain significance (May 18, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002503353.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (6) PubMed: 11861413‚ 27247418‚ 29300372‚ 29121657‚ 27532257‚ 28518168 Number of individuals with the variant: 1 Secondary finding: no
Uncertain significance (Jul 16, 2021)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	- Hypertrophic cardiomyopathy 1 Affected status: unknown Allele origin: inherited	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV002548725.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Comment: The inherited c.5326A>G (p.Ser1776Gly) variant identified in the MYH7 gene substitutes a very well conserved Serine for Glycine at amino acid 1776/1936 (exon 37/40). This … (more) The inherited c.5326A>G (p.Ser1776Gly) variant identified in the MYH7 gene substitutes a very well conserved Serine for Glycine at amino acid 1776/1936 (exon 37/40). This variant is found with low frequency in gnomAD(v3.1.1)(8 heterozygotes, 0 homozygotes; allele frequency: 5.256e-5) suggesting that it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score:0.776) to the function of the canonical transcript. This variant has been reviewed by ClinGen's Cardiomyopathy Variant Curation Expert Panel classified as a Variant of Uncertain Significance in ClinVar (VarID:177629). The c.5326A>G (p.Ser1776Gly) variant has been reported in multiple individuals with hypertrophic cardiomyopathy [PMID:11861413, 21239446, 31199839, others], and segregated with disease in one set of siblings [PMID:11861413]. However, this variant has also been detected in control populations [PMID:24510615], and functional studies suggest it does not alter the ability to bind myosin-binding protein C[PMID:16918501], although additional studies are needed to confirm this finding. Given conflicting evidence regarding its pathogenicity, the inheritedc.5326A>G (p.Ser1776Gly) variant identified in the MYH7 gene is reported as a Variant of Uncertain Significance. (less) Clinical Features: Hypertrophic cardiomyopathy (present) , Left ventricular outflow tract obstruction (present) Zygosity: 1 Single Heterozygote Secondary finding: no
Uncertain significance (Oct 07, 2021)	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: SCV000896386.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Oct 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	- Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Invitae Accession: SCV000546233.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (7) PubMed: 28492532‚ 11861413‚ 27247418‚ 27532257‚ 28518168‚ 29121657‚ 16918501 Comment: This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1776 of the MYH7 protein (p.Ser1776Gly). … (more) This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1776 of the MYH7 protein (p.Ser1776Gly). This variant is present in population databases (rs369437262, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11861413, 27247418, 27532257, 28518168, 29121657). ClinVar contains an entry for this variant (Variation ID: 177629). 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. Experimental studies have shown that this missense change does not substantially affect MYH7 function (PMID: 16918501). 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 (Jan 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- not provided Affected status: unknown Allele origin: germline	PerkinElmer Genomics Accession: SCV003817739.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023
Uncertain significance (May 25, 2022)	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: SCV001333066.3 First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (Oct 31, 2022)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	- Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000736987.5 First in ClinVar: Apr 14, 2018 Last updated: Apr 15, 2023	Publications: PubMed (10) PubMed: 24510615‚ 27247418‚ 27532257‚ 28518168‚ 29121657‚ 30731207‚ 30847666‚ 31199839‚ 31493341‚ 34542152 Comment: The p.S1776G variant (also known as c.5326A>G), located in coding exon 35 of the MYH7 gene, results from an A to G substitution at nucleotide … (more) The p.S1776G variant (also known as c.5326A>G), located in coding exon 35 of the MYH7 gene, results from an A to G substitution at nucleotide position 5326. The serine at codon 1776 is replaced by glycine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy cohorts, although, in some cases, clinical details were limited or it co-occurred with other variants (Fokstuen S et al. J Med Genet. 2011;48(8):572-6; Homburger JR et al. Proc Natl Acad Sci U.S.A. 2016 06;113(24):6701-6; Viswanathan SK et al. PLoS ONE. 2017;12(11):e0187948; Walsh R et al. Genet Med. 2017 02;19(2):192-203). In one study, this variant co-segregated with disease in two affected siblings (Blair E et al. Circ Res. 2002;90(3):263-9). This variant has also been seen in an exome cohort, a control cohort, and a biobank cohort but cardiovascular history was not provided (Pan S et al. Circ Cardiovasc Genet. 2012 5(6):602-10; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Park J et al. Hum Mol Genet. 2022 03;31(5):827-837). This variant is located in the LMM protein domain, involved in thick filament assembly supporting contractile function. One in vitro functional study indicated this variant did not disrupt binding to myosin binding protein C, but may affect thick filament structure and stability; however, the physiological relevance of this finding is unclear (Flashman E et al. Biochem J. 2007;401(1):97-102). 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 variant remains unclear. (less)
Uncertain significance (May 01, 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: SCV001572358.2 First in ClinVar: May 01, 2021 Last updated: Jun 24, 2023	Publications: PubMed (12) PubMed: 16918501‚ 11861413‚ 21239446‚ 27247418‚ 27532257‚ 29121657‚ 29300372‚ 31199839‚ 30847666‚ 30731207‚ 34137518‚ 34136434 Comment: Variant summary: MYH7 c.5326A>G (p.Ser1776Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of … (more) Variant summary: MYH7 c.5326A>G (p.Ser1776Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251494 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5326A>G has been reported in the literature in individuals affected with HCM (Blair_2002, Fokstuen_2011, Homburger_2017, Walsh_2017, Viswanathan_2017, Kelly_2018, Daoud_2019, vanLint_2019, AlShafai_2021) including reports of co-occurrences of this variant with other pathogenic variants. One study showed limited evidence indicating this variant may segregate with disease (Blair_2002). However, these reports do not provide unequivocal conclusions about association of the variant with HCM. One in vitro study showed that this variant does not affect cMyBP-C attachment to the thick filament, showing no damaing effect of this variant in this context (Flashman_2007). The following publications have been ascertained in the context of this evaluation (PMID: 34137518, 11861413, 30731207, 16918501, 21239446, 27247418, 34136434, 29300372, 31199839, 29121657, 27532257, 30847666). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Apr 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001359756.3 First in ClinVar: Jun 22, 2020 Last updated: Jan 08, 2022	Comment: This missense variant replaces serine with glycine at codon 1776 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces serine with glycine at codon 1776 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). A functional study has shown that this variant does not affect cMyBP-C attachment to the thick filament (PMID: 16918501). This variant has been reported in two individuals of a single family affected with hypertrophic cardiomyopathy (PMID: 11861413) and in four unrelated individuals with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 29121657, 31493341). This variant has also been identified in 13/282892 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 (Sep 30, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	- Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000208629.11 First in ClinVar: Jan 31, 2015 Last updated: Mar 04, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by the ClinGen … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (SCV000564457.4; ClinVar Variant ID#177629; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16918501, 29300372, 21239446, 11861410, 25961035, 11861413, 27247418, 23074333, 27532257, 24510615, 29121657, 28518168, 30297972, 31493341, 32420109, 30847666) (less)
Uncertain significance (Jan 06, 2015)	no assertion criteria provided Method: clinical testing	- not specified Affected status: not provided Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280364.1 First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015	Comment: Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more) Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1776Gly (AGC>GGC): c.5326 A>G in exon 37 of the MYH7 gene (NM_000257.2) We first reviewed this variant in 2011. We re-reviewed them October 15th, 2014 and then again February 20th, 2015. Given the high frequency of Filipino cases and lack of ancestry matched controls we consider this a variant of uncertain significance. The variant has been seen in two published cases of HCM and at least 15 unpublished cases (not including the patient). Ancestry is only available for 11 cases (including this patient); 5 are Asian, 6 are Filipino of those are Asian, as is this patient. At least 4 of 16 total cases (including ours) have another sarcomere variant. This variant has been reported previously in two unrelated cases of HCM (Blair et al 2002, Fokstuen et al 2010). In the family reported by Blair et al (2002) the variant was present in two affected siblings and absent in an unaffected sibling (ancestry not reported). The proband underwent analysis of MYH7, MYBPC3, TNNT2, ACTC2, MYL2 and had no variants in those genes. Cases were recruited in the UK and South Africa.Fokstuen et al (2010) observed the variant in 1 of 122 unrelated HCM patients recruited in Switzerland. They did not provide segregation data. Subjects underwent sequencing of MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC1, TNNC1, PRKAG2, however the authors do not report if any cases had multiple variants. We have seen the variant in one other patient with HCM in our center who is Fillipino. This is a semi conservative amino acid change with a polar Serine replaced with a nonpolar Glycine at codon 1776 of MYH7 gene. The Serine at position 1776 is conserved across mammals and myosin isoforms. Given that this amino acid change is located in a core position of the myosin rod, where a Glycine is expected to be energetically unfavorable, Blair et al (2002) hypothesized that this variant would disrupt the normal coiled-coil structure of myosin. However, this variant did not interfere with binding to myosin binding protein C (Flasshman et al 2007). Variants in nearby codons have been reported in association with cardiomyopathy: p.Glu1768Lys (van Driest et al 2003), p.Thr1775Ile (Bos et al 2014), p.Ala1777Thr (Richard et al 2003, Bos et al 2014), p.His1778Tyr (Alfares et al 2015), . The variant was reported online in 4 of 60705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 23rd, 2015). Specifically, the variant was observed in 2 of 4327 East Asians and 2 of 5203 Africans, . The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Blair et al (2002) report they did not observe the variant in 200 presumably healthy control individuals. Fokstuen et al (2010) did not analyze teh variant in controls. (less) Number of individuals with the variant: 17

Comment:

The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID: 30297972) but has also been identified in 0.02% (2/8654) of East Asian chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). 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 uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3

Comment:

The p.Ser1776Gly variant in MYH7 has been identified in at least 12 individuals with HCM (Blair 2002, Fokstuen 2010, Homburger 2016, Walsh 2017, Kelly 2018, Ho 2018, LMM data) and segregated with disease in 1 affected family member (Blair 2 002). It has also been identified in 0.03% (6/19954) of East Asian and 0.02% (5/ 24968) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Comp utational prediction tools and conservation analysis suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. Moreover, this variant was classified as a variant of uncert ain significance on December 15, 2016 by the ClinGen-approved Inherited Cardiomy opathy expert panel (SCV000564457.2). In summary, the clinical significance of t he p.Ser1776Gly variant is uncertain due to conflicting evidence. ACMG/AMP Crite ria applied: PP3.

Comment:

The inherited c.5326A>G (p.Ser1776Gly) variant identified in the MYH7 gene substitutes a very well conserved Serine for Glycine at amino acid 1776/1936 (exon 37/40). This variant is found with low frequency in gnomAD(v3.1.1)(8 heterozygotes, 0 homozygotes; allele frequency: 5.256e-5) suggesting that it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score:0.776) to the function of the canonical transcript. This variant has been reviewed by ClinGen's Cardiomyopathy Variant Curation Expert Panel classified as a Variant of Uncertain Significance in ClinVar (VarID:177629). The c.5326A>G (p.Ser1776Gly) variant has been reported in multiple individuals with hypertrophic cardiomyopathy [PMID:11861413, 21239446, 31199839, others], and segregated with disease in one set of siblings [PMID:11861413]. However, this variant has also been detected in control populations [PMID:24510615], and functional studies suggest it does not alter the ability to bind myosin-binding protein C[PMID:16918501], although additional studies are needed to confirm this finding. Given conflicting evidence regarding its pathogenicity, the inheritedc.5326A>G (p.Ser1776Gly) variant identified in the MYH7 gene is reported as a Variant of Uncertain Significance.

Comment:

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1776 of the MYH7 protein (p.Ser1776Gly). This variant is present in population databases (rs369437262, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11861413, 27247418, 27532257, 28518168, 29121657). ClinVar contains an entry for this variant (Variation ID: 177629). 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. Experimental studies have shown that this missense change does not substantially affect MYH7 function (PMID: 16918501). 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 p.S1776G variant (also known as c.5326A>G), located in coding exon 35 of the MYH7 gene, results from an A to G substitution at nucleotide position 5326. The serine at codon 1776 is replaced by glycine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy cohorts, although, in some cases, clinical details were limited or it co-occurred with other variants (Fokstuen S et al. J Med Genet. 2011;48(8):572-6; Homburger JR et al. Proc Natl Acad Sci U.S.A. 2016 06;113(24):6701-6; Viswanathan SK et al. PLoS ONE. 2017;12(11):e0187948; Walsh R et al. Genet Med. 2017 02;19(2):192-203). In one study, this variant co-segregated with disease in two affected siblings (Blair E et al. Circ Res. 2002;90(3):263-9). This variant has also been seen in an exome cohort, a control cohort, and a biobank cohort but cardiovascular history was not provided (Pan S et al. Circ Cardiovasc Genet. 2012 5(6):602-10; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Park J et al. Hum Mol Genet. 2022 03;31(5):827-837). This variant is located in the LMM protein domain, involved in thick filament assembly supporting contractile function. One in vitro functional study indicated this variant did not disrupt binding to myosin binding protein C, but may affect thick filament structure and stability; however, the physiological relevance of this finding is unclear (Flashman E et al. Biochem J. 2007;401(1):97-102). 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 variant remains unclear.

Comment:

Variant summary: MYH7 c.5326A>G (p.Ser1776Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251494 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5326A>G has been reported in the literature in individuals affected with HCM (Blair_2002, Fokstuen_2011, Homburger_2017, Walsh_2017, Viswanathan_2017, Kelly_2018, Daoud_2019, vanLint_2019, AlShafai_2021) including reports of co-occurrences of this variant with other pathogenic variants. One study showed limited evidence indicating this variant may segregate with disease (Blair_2002). However, these reports do not provide unequivocal conclusions about association of the variant with HCM. One in vitro study showed that this variant does not affect cMyBP-C attachment to the thick filament, showing no damaing effect of this variant in this context (Flashman_2007). The following publications have been ascertained in the context of this evaluation (PMID: 34137518, 11861413, 30731207, 16918501, 21239446, 27247418, 34136434, 29300372, 31199839, 29121657, 27532257, 30847666). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This missense variant replaces serine with glycine at codon 1776 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). A functional study has shown that this variant does not affect cMyBP-C attachment to the thick filament (PMID: 16918501). This variant has been reported in two individuals of a single family affected with hypertrophic cardiomyopathy (PMID: 11861413) and in four unrelated individuals with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 29121657, 31493341). This variant has also been identified in 13/282892 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:

In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (SCV000564457.4; ClinVar Variant ID#177629; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16918501, 29300372, 21239446, 11861410, 25961035, 11861413, 27247418, 23074333, 27532257, 24510615, 29121657, 28518168, 30297972, 31493341, 32420109, 30847666)

Comment:

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1776Gly (AGC>GGC): c.5326 A>G in exon 37 of the MYH7 gene (NM_000257.2) We first reviewed this variant in 2011. We re-reviewed them October 15th, 2014 and then again February 20th, 2015. Given the high frequency of Filipino cases and lack of ancestry matched controls we consider this a variant of uncertain significance. The variant has been seen in two published cases of HCM and at least 15 unpublished cases (not including the patient). Ancestry is only available for 11 cases (including this patient); 5 are Asian, 6 are Filipino of those are Asian, as is this patient. At least 4 of 16 total cases (including ours) have another sarcomere variant. This variant has been reported previously in two unrelated cases of HCM (Blair et al 2002, Fokstuen et al 2010). In the family reported by Blair et al (2002) the variant was present in two affected siblings and absent in an unaffected sibling (ancestry not reported). The proband underwent analysis of MYH7, MYBPC3, TNNT2, ACTC2, MYL2 and had no variants in those genes. Cases were recruited in the UK and South Africa.Fokstuen et al (2010) observed the variant in 1 of 122 unrelated HCM patients recruited in Switzerland. They did not provide segregation data. Subjects underwent sequencing of MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC1, TNNC1, PRKAG2, however the authors do not report if any cases had multiple variants. We have seen the variant in one other patient with HCM in our center who is Fillipino. This is a semi conservative amino acid change with a polar Serine replaced with a nonpolar Glycine at codon 1776 of MYH7 gene. The Serine at position 1776 is conserved across mammals and myosin isoforms. Given that this amino acid change is located in a core position of the myosin rod, where a Glycine is expected to be energetically unfavorable, Blair et al (2002) hypothesized that this variant would disrupt the normal coiled-coil structure of myosin. However, this variant did not interfere with binding to myosin binding protein C (Flasshman et al 2007). Variants in nearby codons have been reported in association with cardiomyopathy: p.Glu1768Lys (van Driest et al 2003), p.Thr1775Ile (Bos et al 2014), p.Ala1777Thr (Richard et al 2003, Bos et al 2014), p.His1778Tyr (Alfares et al 2015), . The variant was reported online in 4 of 60705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 23rd, 2015). Specifically, the variant was observed in 2 of 4327 East Asians and 2 of 5203 Africans, . The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Blair et al (2002) report they did not observe the variant in 200 presumably healthy control individuals. Fokstuen et al (2010) did not analyze teh variant in controls.

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 this variant

Title	Author	Journal	Year	Link
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
Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs.	Al-Shafai KN	Molecular genetics & genomic medicine	2021	PMID: 34137518
Strategies in Rapid Genetic Diagnostics of Critically Ill Children: Experiences From a Dutch University Hospital.	Imafidon ME	Frontiers in pediatrics	2021	PMID: 34136434
Hypertrophic cardiomyopathy in a lupus patient: a case of hydroxychloroquine cardiotoxicity.	Chang A	ESC heart failure	2019	PMID: 31493341
Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging.	Miller RJH	PloS one	2019	PMID: 31199839
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Genetic Diagnostic Testing for Inherited Cardiomyopathies: Considerations for Offering Multi-Gene Tests in a Health Care Setting.	Daoud H	The Journal of molecular diagnostics : JMD	2019	PMID: 30731207
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).	Ho CY	Circulation	2018	PMID: 30297972
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	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29300372
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.	Viswanathan SK	PloS one	2017	PMID: 29121657
Using high-resolution variant frequencies to empower clinical genome interpretation.	Whiffin N	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28518168
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.	Nykamp K	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28492532
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
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
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	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise.	Kapplinger JD	Journal of cardiovascular translational research	2014	PMID: 24510615
Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice.	Fokstuen S	Journal of medical genetics	2011	PMID: 21239446
Localization of the binding site of the C-terminal domain of cardiac myosin-binding protein-C on the myosin rod.	Flashman E	The Biochemical journal	2007	PMID: 16918501
Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy.	Bohlega S	Neurology	2004	PMID: 15136674
Mutations of the light meromyosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy.	Blair E	Circulation research	2002	PMID: 11861413
Beta-myosin heavy chain gene mutations in familial hypertrophic cardiomyopathy: the usual suspect?	McNally EM	Circulation research	2002	PMID: 11861410
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5d9a840f-4e17-4378-a41d-341cf6eab7b8	-	-	-	-

Text-mined citations for rs369437262...

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Record last updated Aug 13, 2023

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.5326A>G (p.Ser1776Gly)

NM_000257.4(MYH7):c.5326A>G (p.Ser1776Gly)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs369437262...