rs727503258

Positions:

• chr14-23425358-G-A
• chr14-23425358-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM5 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):​c.2347C>T​(p.Arg783Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,890 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R783H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 0.443

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000257.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23425357-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 14-23425358-G-A is Pathogenic according to our data. Variant chr14-23425358-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181182.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2347C>T	p.Arg783Cys	missense_variant	21/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2347C>T	p.Arg783Cys	missense_variant	20/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2347C>T	p.Arg783Cys	missense_variant	21/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

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: 0.00000547 AC: 8 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 03, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg783 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21211974). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 181182). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). This variant is present in population databases (rs727503258, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 783 of the MYH7 protein (p.Arg783Cys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Arg783Cys variant in MYH7 has been identified in 1 individual with HCM (Homburger 2016). It has been identified in 1/113752 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar (Variation ID: 181182). Computational prediction tools and conservation analysis suggest that the p.Arg783His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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 addition, 2 other variants involving this codon, p.Arg783His and p.Arg783Pro, have been identified in individuals with cardiomyopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PP3. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2023	Reported in association with HCM in published literature; however, detailed clinical information was not provided (Homburger et al., 2016; Bonaventure et al., 2019); 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: 31589614, 34135346, 27532257, 29300372, 27247418, 31110529, 30275503) -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This missense variant replaces arginine with cysteine at codon 783 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 31110529). Different variants affecting the same codon, p.Arg783His and p.Arg783Pro, are considered to be disease-causing (ClinVar variation ID: 180437 and 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 1/251474 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 02, 2023	This missense variant replaces arginine with cysteine at codon 783 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 31110529). Different variants affecting the same codon, p.Arg783His and p.Arg783Pro, are considered to be disease-causing (ClinVar variation ID: 180437 and 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 1/251474 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2024

The p.R783C variant (also known as c.2347C>T), located in coding exon 19 of the MYH7 gene, results from a C to T substitution at nucleotide position 2347. The arginine at codon 783 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 has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Robert-Paganin J et al. Nat Commun, 2018 Oct;9:4019; Bonaventura J et al. Arch Med Sci, 2019 May;15:641-649; Bonaventura J et al. J Am Heart Assoc, 2024 May;13:e033565). Another variant at the same codon, p.R783H (c.2348G>A), has been detected in numerous individual from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing (Waldmüller S et al. Clin. Chem., 2008 Apr;54:682-7; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Jääskeläinen P et al. ESC Heart Fail. 2019 Apr;6(2):436-445; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126; Phan PD et al. JRSM Cardiovasc Dis. 2024 Jan;13:20480040231220100; Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.10
Eigen_PC	Benign	-0.0025
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.82	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.032	D
Polyphen		0.97	D
Vest4		0.82
MutPred		0.59		Gain of catalytic residue at R787 (P = 0.0054);
MVP		0.98
MPC		2.2
ClinPred		0.92	D
GERP RS		2.7
Varity_R		0.40
gMVP		0.93

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

Other links and lift over

dbSNP: rs727503258; hg19: chr14-23894567; COSMIC: COSV100805719;