14-23427657-C-T

Position:

chr14-23427657-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.1816G>A(p.Val606Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V606L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29O:1

Conservation

PhyloP100: 2.54

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 Pathogenic. Variant got 17 ACMG points.

PM1

In a helix (size 7) in uniprot entity MYH7_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23427657-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 14-23427657-C-T is Pathogenic according to our data. Variant chr14-23427657-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23427657-C-T is described in Lovd as [Pathogenic]. Variant chr14-23427657-C-T is described in Lovd as [Pathogenic]. Variant chr14-23427657-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.1816G>A	p.Val606Met	missense_variant	16/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.1816G>A	p.Val606Met	missense_variant	15/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.1816G>A	p.Val606Met	missense_variant	16/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251476

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:29Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 01, 2013	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.Val606Met (c.1816 G>A) in MYH7 This variant has been reported in more than 17 unrelated individuals with HCM. With strong segregation data and a transgenic mouse model The Seidman team first reported the variant in three families with a Lod score of 3.5 (Watkins et al 1992), though unfortunately the authors do not report how many affected individuals had the variant in each family. The same group later published on eight affected individuals with this variant, presumably from the same three families initially reported (Solomon et al 1993). Fananapazir et al (1994) reported two additional cases with this variant with at least four family members segregating the variant and disease. Marian et al (1995) reported a family in which all 8 individuals with HCM and 1 obligate carrier carried p.Val606Met (likely the same family as reported in Abchee et al 1997, though only abstract is available). Nakajima-Taniguchi et al (1995) observed the variant in a Japanese man with HCM. Semsarian et al (1997) described an Australian patient with HCM. Greber-Platzer et al (2001) reported a family with four affected family members who all carried this variant. Havndrup et al (2001, 2003) reported a Danish family with four family members with HCM who all carried this variant. Blair et al (2001) reported a family in which two individuals with HCM had p.Val606Met. They also had p.Ala728Val and the two were thought to be in cis. Richard et al (2003) reported the variant in one HCM patient in their French cohort. Ingles et al reported the variant in a patient with HCM from their Australian cohort and based on how they label their pedigrees, this seems to be different case from the one reported by Semsarian et al (1997). Yuan et al (2008) reported a Chinese family with four affected members with p.Val606Met. Overeem et al (2007) reported a family with p.Val606Met that had both HCM and a distal skeletal myopathy. Yu et al (2005) reported the variant in an Australian patient that seems to be distinct from the Ingles et al and Semsarian et al reports. Morita et al (2008) reported the variant in a child with HCM from the American pediatric cardiomyopathy registry. Kubo et al (2007) reported the variant in a patient with HCM from their British cohort. Zheng et al (2010) reported a Chinese family in which all three members with HCM had this variant (this seems to be distinct from the family reported by Yuan et al 2008). Millat et al (2010) identified the variant in 2 individuals with HCM from their French cohort, which seems to be distinct from the case reported by Richard et al (2003). Cuda et al (1997) demonstrated that purified myosin from patients with p.Val606Met had decreased actin sliding velocities. A review by Walsh et al (2010) and a presentation by the Seidman group online both refer to a mouse model using p.Val606Met that recapitulates HCM, however I could not find the primary reference. The Valine at codon 606 is highly, though not completely conserved across species (there is a Proline at this codon in Rhesus monkeys). In silico analysis with polyphen 2 predicts the variant to be probably damaging. Another variant at the same codon has been reported in association with HCM (p.Val606Leu, Waldmuller et al 2002), as have variants at nearby codons (p.Lys611Asn (Seidman group, online), p.Asn602Ser (Marian et al 1995, Koyanagi et al 1996), p.Leu601Val (Havndrup et al 2003). The variant as absent in a total of 470 published controls including 100 (Havndrup et al 2001), 100 (Richard et al 2003), 150 (Ingles et al 2005), 120 (Yuan et al 2008). Early studies did not report control data. The variant is not currently listed in the NHLBI Exome S -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MYH7: PP1:Strong, PM2, PM5, PS4:Moderate, PP2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 24093860, 18403758, 27247418, 25351510, 20624503, 30775854, 24829265, 21769673, 19100006, 11377367, 1552912, 27483260, 9826622, 21310275, 27532257, 29101517, 7789380, 11133230, 20819418, 28971120, 30025578, 17383184, 15858117, 8981935, 30554920, 29398688, 31513939, 31996869, 32217077, 32344918, 31983222, 31737537, 12707239, 8281650, 31589614, 33673806, 32894683, 9172070, 29300372) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2021	The MYH7 c.1816G>A; p.Val606Met variant (rs121913627) is reported in the literature in numerous individuals and families affected with hypertrophic cardiomyopathy (HCM) (Arad 2014, Greber-Platzer 2001, Havndrup 2001, Watkins 1992, Zheng 2010). This variant has been found to co-segregate with disease in multiple families, although it also exhibits variable penetrance and expressivity (Arad 2014, Greber-Platzer 2001, Havndrup 2001, Watkins 1992, Zheng 2010). This variant is found on only two chromosomes in the Genome Aggregation Database (2/282868 alleles), indicating it is not a common polymorphism. The valine at codon 606 is highly conserved, it occurs in the myosin motor domain, and functional studies suggest the variant protein has altered kinetics compared to wildtype protein (Roopnarine 1998). A mouse model expressing the p.Val606Met variant exhibits largely normal cardiac function alone but develops mild HCM in response to cyclosporine and leads to a severe HCM phenotype in combination with another MYH7 variant (Blankenburg 2014). Based on available information, the p.Val606Met variant is considered to be pathogenic. References: Arad M et al. Merits and pitfalls of genetic testing in a hypertrophic cardiomyopathy clinic. Isr Med Assoc J. 2014;16(11):707-713. Blankenburg R et al. Beta-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations. Circ Res. 2014;115(2):227-237. Greber-Platzer S et al. Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children. J Mol Cell Cardiol. 2001;33(1):141-148. Havndrup O et al. The Val606Met mutation in the cardiac beta-myosin heavy chain gene in patients with familial hypertrophic cardiomyopathy is associated with a high risk of sudden death at young age. Am J Cardiol. 2001;87(11):1315-1317. Roopnarine O and Leinwand LA. Functional analysis of myosin mutations that cause familial hypertrophic cardiomyopathy. Biophys J. 1998;75(6):3023-3030. Watkins H et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992;326(17):1108-1114. Zheng DD et al. Mutations in the beta-myosin heavy chain gene in southern Chinese families with hypertrophic cardiomyopathy. J Int Med Res. 2010;38(3):810-820. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Hypertrophic cardiomyopathy 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID 29300372). (I) 0115 - Variants in this gene are known to have variable expressivity. Patients with this specific variant have been reported with varying severity, from mild hypertrophic cardiomyopathy to sudden cardiac death (ClinVar). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional myosin head domain (PMID 29300372). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic many times, and in over 20 patients with hypertrophic cardiomyopathy with varying severity (ClinVar, LOVD, PMID: 30775854). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Oct 30, 2014	This MYH7 Val606Met variant has previously been described in HCM patients. Co-segregation of this variant with disease has been demonstrated in multiple unrelated families, with complete disease penetrance observed in relatives of the proband (Watkins H., et al 1992; Fananapazir L., et al 1994; Havndrup O., et al 2001) . Disease manifestation associated with this variant are markedly variable amongst individuals and between unrelated families. Watkins H., et al (1992) report their family to have "near normal survival" whereas Havndrup O., et al (2001) report a family with the same MYH7 Val606Met mutation to have unfavourable outcomes with high risk of sudden cardiac death. We have observed the Val606Met mutation in two HCM families (Ingles J., et al 2005) and have shown that it segregates with disease. Therefore, this variant is categorised by our group as "pathogenic" based on available literature and familial segregation analysis where possible. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 27, 2022	- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	Jun 01, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 25, 2016	- -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2020	The p.Val606Met variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 15 affected individuals from multiple families (Watkins 1992 PMID: 1552912, Solomon 1993 PMID: 8335820, Fananapazir 1994 PMID: 8281650, Marian 1995 PMID: 7789380, Richard 2003 PMID: 12707239, Greber-Platzer 2001 PMID: 11133230, Blair 2001 PMID: 11424919, Havndrup 2001 PMID: 11377367, Havndrup 2003 PMID: 12566107, Ingles 2005 PMID: 16199542, Jacques 2008 PMID: 18411228, Zheng 2010 PMID: 20819418, LMM data). It should be noted, however, that this variant is associated with variable presentation, including the age at onset and with different outcomes in different families (Fananapazir 1994 PMID: 8281650, Nakajima-Taniguchi 1995 PMID: 8788376, Fananapazir 1997 PMID: 9058851, Havndrup 2001 PMID: 11377367). It has also been identified in 0.002% (2/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 14091). Computational prediction tools and conservation analyses are consistent with pathogenicity. Animal models in mice suggest that this variant can result in HCM (Blankenburg 2014 PMID: 24829265). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS3, PS4, PP1_Strong, PM2, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 606 of the MYH7 protein (p.Val606Met). This variant is present in population databases (rs121913627, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 1552912, 9271024, 11133230, 11377367, 15858117, 20624503, 20819418, 24111713). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14091). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 9172070, 9826622, 18020371, 21769673, 24829265). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2021	This missense variant replaces valine with methionine at codon 606 in the actin-binding domain 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). Functional studies have shown the mutant protein to exhibit partially reduced ATPase activity (PMID: 9826622) and motility (PMID: 9172070). This variant caused mild hypertrophic cardiomyopathy in transgenic mice (PMID: 24829265). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 11133230, 25558701, 1552912, 20819418, 21769673, 9271024, 11377367, 20624503, 24111713, 24835277, 27483260, 30775854). This variant has been shown to segregate with hypertrophic cardiomyopathy in 32 individuals from 6 different families (PMID: 1552912, 11133230, 20819418, 25558701). This variant has been identified in 2/282868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 24, 2019	- -

Myosin storage myopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 27, 2022	- -

Cardiovascular phenotype

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2022	The p.V606M pathogenic mutation (also known as c.1816G>A), located in coding exon 14 of the MYH7 gene, results from a G to A substitution at nucleotide position 1816. The valine at codon 606 is replaced by methionine, 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 mutation has been described in several individuals with hypertrophic cardiomyopathy (HCM); however, it initially was detected in 3 unrelated kindreds with familial HCM, reportedly segregating with disease in all 18 affected family members across the 3 families with a combined LOD score of 3.5 (Watkins H et al. N. Engl. J. Med.1992;326:1108-1114; Berge KE et al. Clin Genet. 2014;86(4):355-60; Bagnall RD et al. J Am Col Cardiol. 2018;72(4):419-429; Jääskeläinen P. ESC Heart Fail. 2019 Feb). One of the families originally described by Watkins et al was further described, noting that the index patient and three family members with HCM and this alteration also had distal myopathy while others had HCM only (Overeem S et al. Neuromuscul. Disord. 2007;17(6):490-493). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2017	Variant summary: The MYH7 c.1816G>A (p.Val606Met) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the P-loop containing nucleoside triphosphate hydrolase domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC and a control cohort from the literature (0/121586 control chromosomes). The variant was reported in multiple HCM pts (associated with longer survival compared with other DVs such as R453C and R403Q) by independent literature reports. Functional studies (Blankenburg_Circulation Research_2014; Tripathi_Basic Res Cardiol_2011; Roopnarine_BJ_1998; and Cuda_JMRCM_1997) showed lower in vitro motility activity, decreased actin-activated ATPase activity, allelic imbalance, and a mouse model study showed that the variant causes very mild hypertrophic cardiomyopathy in mice, but the HCM phenotype becomes much more severe with the presence of another HCM mutation. Additionally, the variant has been found segregating with disease in several ethnically diverse families with HCM (Watkins_NEJM_1992; Arad_IMAJ_2014, for example). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. It should be noted that the variant of interest has had conflicting reports regarding phenotypic association, indicating that there is variability in the phenotypes or incomplete penetrance associated with this mutation, which could be due to the effect of modifier genes and environmental factors. However, based on the enrichment of the variant in HCM patients and functional studies, the variant is classified as pathogenic. -

Dilated cardiomyopathy 1S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 27, 2022

- -

MYH7-related skeletal myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 27, 2022

- -

Myopathy, myosin storage, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 27, 2022

- -

MYH7-related disorder

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Pathogenic and reported on 12-18-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.94

Vest4

0.59

MutPred

0.80

Gain of catalytic residue at L608 (P = 0.0146);

MVP

0.96

MPC

2.1

ClinPred

0.97

GERP RS

5.1

Varity_R

0.77

gMVP

0.63

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