rs202141173

Positions:

chr14-23424842-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PS4PP1_ModeratePM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.2606G>A (p.Arg869His) variant has been identified in >30 individuals with HCM, including at least 2 individuals with an additional variant in another gene that may contribute to their disease (PS4; Van Driest 2004 PMID:15358028; Girolami 2006 PMID:16858239; Cecchi 2006 PMID:17180650; Olivotto 2008 PMID:18533079; Girolami 2010 PMID:20359594; Olivotto 2011 PMID:21835430; Witjas-Paalberends 2013 PMID:23674513; Marsiglia 2013 PMID:24093860; Bos 2014 PMID:24793961; Coppini 2014 PMID:25524337; Adalsteinsdottir 2014 PMID:25078086; Homburger 2016 PMID:27247418; Viswanathan 2017 PMID:29121657; Walsh 2017 PMID:2753225; Ho 2018 PMID:30297972; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 6 affected relatives with HCM from at least two families (PP1_Moderate; Girolami 2010 PMID:20359594; GeneDx pers. comm.). Additionally, this variant has also been reported in 1 individual with DCM with an additional variant in another gene that may contribute to their disease, 1 individual with LVH and suspected HCM, 1 individual with LVNC, 1 individual with septal hypertrophy with AV conduction defect, and 4 individuals with unspecified heart disease (Ambry pers. comm.; GenDx pers. comm.). This variant was identified in 0.002% (FAF 95% CI; 2/16254) of African chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but has also been identified in a greater number of African chromosomes in gnomAD v.3.1. Therefore, the PM2 criterion was downgraded to PM2_supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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, PP1_Moderate, PM2_Supporting, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012723/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:18U:1

Conservation

PhyloP100: 0.918

Variant links:

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2606G>A	p.Arg869His	missense_variant	22/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.2606G>A	p.Arg869His	missense_variant	21/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2606G>A	p.Arg869His	missense_variant	22/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251440

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:18Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25078086, 22763267, 24093860, 25351510, 20359594, 25524337, 9172070, 31112422, 30297972, 22958901, 10024460, 18533079, 15358028, 21835320, 24793961, 27247418, 26332594, 27532257, 23674513, 29121657, 29875424, 31447099, 32894683) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 08, 2021	PS4, PM1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 05, 2021	- -

Hypertrophic cardiomyopathy

Pathogenic:4

Likely pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Sep 28, 2021	The NM_000257.4(MYH7):c.2606G>A (p.Arg869His) variant has been identified in >30 individuals with HCM, including at least 2 individuals with an additional variant in another gene that may contribute to their disease (PS4; Van Driest 2004 PMID: 15358028; Girolami 2006 PMID: 16858239; Cecchi 2006 PMID: 17180650; Olivotto 2008 PMID: 18533079; Girolami 2010 PMID: 20359594; Olivotto 2011 PMID: 21835430; Witjas-Paalberends 2013 PMID: 23674513; Marsiglia 2013 PMID: 24093860; Bos 2014 PMID: 24793961; Coppini 2014 PMID: 25524337; Adalsteinsdottir 2014 PMID: 25078086; Homburger 2016 PMID: 27247418; Viswanathan 2017 PMID: 29121657; Walsh 2017 PMID: 2753225; Ho 2018 PMID: 30297972; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 6 affected relatives with HCM from at least two families (PP1_Moderate; Girolami 2010 PMID: 20359594; GeneDx pers. comm.). Additionally, this variant has also been reported in 1 individual with DCM with an additional variant in another gene that may contribute to their disease, 1 individual with LVH and suspected HCM, 1 individual with LVNC, 1 individual with septal hypertrophy with AV conduction defect, and 4 individuals with unspecified heart disease (Ambry pers. comm.; GenDx pers. comm.). This variant was identified in 0.002% (FAF 95% CI; 2/16254) of African chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but has also been identified in a greater number of African chromosomes in gnomAD v.3.1. Therefore, the PM2 criterion was downgraded to PM2_supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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, PP1_Moderate, PM2_Supporting, PM1. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2019	The p.Arg869His variant in MYH7 has been reported in >15 individuals with HCM and segregated with disease in one affected relative (Song 2005, Olivotto 2008, Girolami 2010, Adalsteinsdottir 2014, Bos 2014, Homburger 2016, Viswanathan 2017, Walsh 2017, LMM data). It has been identified in 6/251440 chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM1, PM2, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 869 of the MYH7 protein (p.Arg869His). This variant is present in population databases (rs202141173, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16858239, 17180650, 18533079, 20359594, 22763267, 23674513, 24093860, 25078086, 27247418, 27532257, 29121657). ClinVar contains an entry for this variant (Variation ID: 177667). 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.Arg869 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 30588760, 32380161), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces arginine with histidine at codon 869 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 40 individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 16858239, 18533079, 20359594, 23674513, 24093860, 24793961, 25078086, 27532257, 29121657, 30297972). Several of these individuals also carried pathogenic variants in the MYBPC3 and TNNI3 genes (PMID: 18533079, 20359594). It has been shown that this variant segregates with disease in several affected individuals across two families (PMID: 20359594; ClinVar SCV001976466.1). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 36203036). This variant has been identified in 6/251440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg869Cys, is considered to be disease-causing (ClinVar variation ID: 181196), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Cardiology unit, Meyer University Hospital	Jan 27, 2020	The MYH7:Arg869His variant has been implicated in HCM in several studies (Van Driest et al, 2004; Girolami et al., 2006, Olivotto et al., 2008; Girolami et al., 2010; Witjas-Paalberens et al., 2013; Marsiglia et al., 2013; Adalsteinsdottir et al., 2014; Bos et al., 2014; Mazzarotto & Girolami et al., 2018). This variant is sufficiently rare in the gnomAD population database (MAF 2.39E-5) to activate the PM2 moderate criteria for rarity as per the ACMG/AMP variant interpretation guidelines adapted for MYH7 variants in cardiomyopathy (Kelly et al., 2018). The Arg869His variant alters a residue within the myosin head, which constitutes a large hotspot for variants with a high prior likelihood of pathogenicity in HCM characterised by etiological fraction >0.95 (Kelly et al., 2018 defines ita s between residues 181-937; Walsh et al., 2019 as 167-931), causing the activation of the PM1 criteria (Kelly et al., 2018). Furthermore, we found evidence of co-segregation with HCM in a large Italian pedigree comprising 7 affected carriers and 1 deceased obligate carrier reported to be affected. This enables activation of the PP1_strong criteria for observing >=7 meioses (Kelly et al., 2018). This variant is also carried by 30 of 1198 unrelated probands with HCM tested at the nearby Careggi University Hospital as opposed to 0 of 356 non-HCM probands tested in the same lab (p=6.22E-4), enabling activation of the PS4_strong criteria (Mazzarotto & Girolami et al., 2018; Kelly et al., 2018). Computational evidence is also to be considered supportive of pathogenicity, as multiple in silico pathogenicity predictors classify this variant as damaging / deleterious, enabling activation of the PP3 criteria supporting pathogenicity. In conclusion, the activation of 2 strong, 2 moderate and 1 supporting criteria in favour of pathogenicity enables classification of the MYH7:Arg869His variant as pathogenic for HCM. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 27, 2019	Variant Summary: MYH7 c.2606G>A (p.Arg869His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928). Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3, PP2). The variant allele was found at a frequency of 2.4e-05 in 251440 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2606G>A has been reported in the literature in several well phenotyped individuals affected with and meeting established clinical criteria for Hypertrophic Cardiomyopathy (HCM) (e.g. Witjas-Paalberends_2013, Adalsteinsdottir_2014, Olivotto_2011, Girolami_2010, Walsh_2017, Ho_2018). Though the variant was reported to co-occur with other pathogenic MYBPC3 variants in two different families, the double heterozygous patients showed an earlier onset of HCM, a more rapid disease progression with a more severe phenotype than heterozygous variant carriers, which might be consistent with an additive effect for the co-occurring variants (Girolami_2010, Olivotto_2011). A recent study reported that the allele frequency of this variant in a cohort of HCM patients is much higher (0.0076; i.e. 42/5526 alleles) than that in controls (6/251440 in gnomAD), suggesting this variant could be associated with HCM (Ho_2018) (ACMG PS4). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant: four times as likely pathogenic and once as uncertain significance. In addition, other variants affecting the same codon, R869C, R869G, R869L, have been reported in HGMD in association with HCM (ACMG PM1). Based on the evidence outlined above the variant was re-classified as likely pathogenic. -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 22, 2023	This missense variant replaces arginine with histidine at codon 869 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 40 individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 16858239, 18533079, 20359594, 23674513, 24093860, 24793961, 25078086, 27532257, 29121657, 30297972). Several of these individuals also carried pathogenic variants in the MYBPC3 and TNNI3 genes (PMID: 18533079, 20359594). It has been shown that this variant segregates with disease in several affected individuals across two families (PMID: 20359594; ClinVar SCV001976466.1). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 36203036). This variant has been identified in 6/251440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg869Cys, is considered to be disease-causing (ClinVar variation ID: 181196), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 28, 2022	- -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000257.4:c.2606G>A (chr14:23424842) in MYH7 was detected in 7 heterozygotes out of 58K WGS Icelanders (MAF= 0,006%). Following imputation in a set of 166K Icelanders (7 imputed heterozygotes) we observed a suggestive association with cardiomyopathy (OR=62,1 , P-value=0,03) using 1974 cases and 365360 controls. This variant has been reported in ClinVar previously as likely pathogenic, pathogenic, and as a variant of uncertain significance. Based on ACMG criteria (PS4, PM2_Supporting, PP1_Moderate, PP5) this variant classifies as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 06, 2017	This c.2606G>A (p.Arg869His) variant in the MYH7 gene has been reported in several patients with hypertrophic cardiomyopathy [PMID 18533079, 20359594, 24793961, 14676227, 27247418, 25078086]. Cosegregation has been reported but no detailed information was available for review [PMID 18533079]. This variant was also reported in a patient with hypertrophic cardiomyopathy diagnosed at 18 years of age [PMID 20359594 ]. The patient carries a frameshift variant in TNNI3 and a missense in MYBPC3, both inherited from the father; and this variant in MYH7, inherited from the mother. The mother had mild asymmetric septal hypertrophy. Additional patients have been reported with a change affecting the same amino acid position (Arg869Cys, Arg869Gly). While not validated for clinical use, computer-based algorithms yield discrepant results regarding the deleterious effect of this p.Arg869His change. However, this variant is highly conserved in mammal. This variant has been observed in 6 heterozygous individuals in the gnomAD database (http://gnomad.broadinstitute.org/variant/14-23894051-C-T). This variant is thus classified as likely pathogenic. -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 21, 2021

- -

MYH7-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2024

The MYH7 c.2606G>A variant is predicted to result in the amino acid substitution p.Arg869His. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (see for example, Table S1, Bos et al. 2014. PubMed ID: 24793961; Table 2, Adalsteinsdottir et al. 2014. PubMed ID: 25078086; Table S5, Viswanathan et al. 2017. PubMed ID: 29121657). Moreover, this variant has been observed to be enriched in the disease cohort in a case-control study for hypertrophic cardiomyopathy (Table S1, Homburger et al. 2016. PubMed ID: 27247418). This variant is reported in six out of ~250,000 alleles in gnomAD. Alternate nucleotide substitutions affecting the same amino acid (p.Arg869Gly, p.Arg869Cys, p.Arg869Pro, and p.Arg869Leu) have been reported in multiple individuals with hypertrophic cardiomyopathy (Table 1, Richard et al. 2000. PubMed ID: 10900182; Table 1, Nakashima et al. 2020. PubMed ID: 32830170; Table S1, Chung et al. 2021. PubMed ID: 33658040; Table S1, Walsh et al. 2017. PubMed ID: 27532257). In summary, the c.2606G>A (p.Arg869His) variant is interpreted as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The p.R869H pathogenic mutation (also known as c.2606G>A), located in coding exon 20 of the MYH7 gene, results from a G to A substitution at nucleotide position 2606. The arginine at codon 869 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM), although clinical details were limited in some cases (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Girolami F et al. J. Am. Coll. Cardiol., 2010 Apr;55:1444-53; Witjas-Paalberends ER et al. Cardiovasc. Res., 2013 Aug;99:432-41; Adalsteinsdottir B et al. Circulation, 2014 Sep;130:1158-67; Lopes LR et al. Heart, 2015 Feb;101:294-301; Ambry internal data). This variant was also reported to segregate with disease in multiple affected family members (Maurizi N et al. JAMA Cardiol, 2018 Jun;3:520-525; external communication). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.82

MVP

0.94

MPC

2.3

ClinPred

0.87

GERP RS

4.7

Varity_R

0.47

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over