rs727503263

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.2011C>T(p.Arg671Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.86

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a strand (size 8) in uniprot entity MYH7_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000257.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.983

PP5

Variant 14-23426810-G-A is Pathogenic according to our data. Variant chr14-23426810-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23426810-G-A is described in Lovd as [Pathogenic]. Variant chr14-23426810-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.2011C>T	p.Arg671Cys	missense_variant	Exon 18 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.2011C>T	p.Arg671Cys	missense_variant	Exon 17 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.2011C>T	p.Arg671Cys	missense_variant	Exon 18 of 40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

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:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:2

Sep 05, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.2011C>T (p.Arg671Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252082 control chromosomes. c.2011C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Mohiddin_2003, Richard_2003, Wang_2014, Zhao_2021, Chida_2017, Walsh_2017). Additionally it was observed de novo patient (Zhao_2021) and in a family with Cardiomyopathy (Chida_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27885498, 12820698, 12707239, 27532257, 25132132, 32381727). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and pathogenic/likely pathogenic (n=7). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 18, 2024

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2011C>T variant in MYH7 causes an amino acid substitution, which replaces arginine with cysteine at position 671. It has not been reported in control populations in the Genome Aggregation Database (gnomAD). It has been previously reported in at least 15 apparently unrelated individuals with hypertrophic cardiomyopathy (PMID 12707239, 12820698, 25132132, 27532257, 27885498, 34345284, 33769460, and others, ClinVar database; CHEO internal data). This variant was reported to segregate with disease in at least four families (PMID 27885498, 34345284, ClinVar database). It was also reported as de novo with unconfirmed parental relationship in an individual with cardiac hypertrophy (PMID 32381727). This variant is located within the head region (codons 181-937) of the Myosin-7 protein (NM_000257.2; NP_000248.2), where MYH7 pathogenic variants are significantly clustered (PMID 29300372). The Arg671 residue is highly conserved across evolutionarily distant species. In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function. This variant is listed in ClinVar (VCV000164350). Based on the above information, we categorize this variant as pathogenic. -

not provided

Pathogenic:2

May 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH7 c.2011C>T; p.Arg671Cys variant (rs727503263; ClinVar ID: 164350) is reported in the literature in multiple individuals and families affected with hypertrophic cardiomyopathy (Alfares 2015, Chida 2017, Richard 2003, Walsh 2017, Wang 2014), including at least one individual in which the variant arose de novo (Zhao 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant occurs in the critical myosin head domain, and computational analyses predict that this variant is deleterious (REVEL: 0.942). Based on available information, this variant is considered to be pathogenic. References: Alfares AA et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8. PMID: 25611685. Chida A et al. Prognostic predictive value of gene mutations in Japanese patients with hypertrophic cardiomyopathy. Heart Vessels. 2017 Jun;32(6):700-707. PMID: 27885498. Richard P et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003 May 6;107(17):2227-32. PMID: 12707239. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. Wang J et al. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. Eur J Heart Fail. 2014 Sep;16(9):950-7. PMID: 25132132. Zhao S et al. Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS). J Med Genet. 2021 Jan;58(1):41-47. PMID: 32381727. -

Aug 16, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Segregated with HCM in one relative of a single proband tested at GeneDx and in two relatives in published literature (PMID: 34345284); Not observed at 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: 12820698, 27532257, 12707239, 21310275, 25132132, 30626765, 27885498, 36143288, 31941943, 31447099, 25611685, 34345284, 28606303, 38377203, 37652022, 37850193, 29300372, 32381727, 36693943) -

Hypertrophic cardiomyopathy

Pathogenic:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 671 of the MYH7 protein (p.Arg671Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 12820698, 25132132, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 164350). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -

Aug 16, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg671Cys variant in MYH7 has been reported in 8 individuals with HCM (Mohiddin 2003, Richard 2003, Wang 2014, Walsh 2017, LMM data). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate, PP3. -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Mar 15, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2011C>T (p.Arg671Cys) variant in the MYH7 gene has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID 12820698, 12707239, 25132132, 27532257) and is not observed in general population databases. This variant is located in the critical myosin head domain of MYH7 and is predicted to be damaging by multiple in silico algorithms. Therefore, this c.2011C>T (p.Arg671Cys) variant in the MYH7 gene is classified as likely pathogenic. -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000164350, PMID:12707239). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:25132132). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942>=0.6, 3CNET: 0.993>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Congenital myopathy with fiber type disproportion

Pathogenic:1

Jul 04, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3. -

Cardiovascular phenotype

Pathogenic:1

Oct 31, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R671C pathogenic mutation (also known as c.2011C>T), located in coding exon 16 of the MYH7 gene, results from a C to T substitution at nucleotide position 2011. The arginine at codon 671 is replaced by cysteine, an amino acid with highly dissimilar 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 variant was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy, including a de novo occurrence, and segregated with disease in at least one family (Mohiddin SA et al. Genet Test. 2003;7(1):21-7; Richard P et al. Circulation. 2003;107(17):2227-32; Wang J et al. Eur J Heart Fail. 2014; 16(9):950-7; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Chida A et al. Heart Vessels. 2017;32:700-707; Walsh R et al. Genet. Med. 2017;19:192-203, Zhao S et al. J. Med. Genet., 2020 May;0:1-7; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Pathogenic

0.99

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.83

Gain of catalytic residue at P675 (P = 0.0044);

MVP

0.99

MPC

2.5

ClinPred

1.0

GERP RS

4.9

Varity_R

0.74

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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