rs730880822

chr14-23415020-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Strong

The NM_000257.4(MYH7):c.5534G>A(p.Arg1845Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,564 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1845W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:6
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a turn (size 3) in uniprot entity MYH7_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23415021-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14114.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 14-23415020-C-T is Pathogenic according to our data. Variant chr14-23415020-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 181286.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.5534G>A	p.Arg1845Gln	missense_variant	37/40	ENST00000355349.4
MYH7	NM_001407004.1	c.5534G>A	p.Arg1845Gln	missense_variant	36/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.5534G>A	p.Arg1845Gln	missense_variant	37/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248590 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457564 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2013	p.Arg1845Gln (CGG>CAG): c.5534 G>A in exon 37 of the MYH7 gene (NM_000257.2). The Arg1845Gln variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg1845Gln results in a semi-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Arg1845Gln is damaging to the protein structure/function. Mutations at this codon (Arg1845Trp) and in nearby residues (Ser1836Leu, Arg1846Cys, Thr1854) have been reported in association with myopathy and cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Arg1845Gln variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Arg1845Gln is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s). -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 26, 2019	This missense variant replaces arginine with glutamine at codon 1845 of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with cardiomyopathy after cancer drug treatment (PMID: 25332820) and in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). A different missense variant occurring at the same codon, p.Arg1845Trp (Clinvar variation ID: 14114) is known to cause myosin storage myopathy and scapuloperoneal myopathy, suggesting that arginine at this position is important for MYH7 protein function. This variant has also been identified in 1/248590 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, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Nov 19, 2021	The NM_000257.4(MYH7):c.5534G>A (p.Arg1845Gln) variant has been identified in 2 individuals with unspecified cardiomyopathy (van Lint FHM 2019 PMID: 30847666; GeneDx pers. comm.), in 1 individual with LVNC (van Waning 2020 PhD Thesis: https://repub.eur.nl/pub/124773/dissertation-van-Waning.pdf) and 1 individual with anthracycline-associated cardiomyopathy (Wasielewski 2014 PMID: 25332820); however, due to the nature of the associated phenotypes, this data is insufficient to apply the PS4 criterion. This variant has also been identified in 0.003% (1/34584) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon; however, it has been reported to cause myosin storage myopathy and the additional evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively (c.5533C>T p.Arg1845Trp- Variation ID 14114). Therefore, the PM5 criterion has not been applied. In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 10, 2022	- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1845 of the MYH7 protein (p.Arg1845Gln). This variant is present in population databases (rs730880822, gnomAD 0.003%). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 181286). 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.Arg1845 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14520662, 15699387, 17118657, 17336526, 19336582, 20376763). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2023

The p.R1845Q variant (also known as c.5534G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5534. The arginine at codon 1845 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in an individual reported to have anthracycline-associated cardiomyopathy and has been detected in a noncompaction cardiomyopathy cohort as well as in an individual tested for unknown cardiomyopathy; however, details were limited (Wasielewski M et al. Open Heart, 2014 Jul;1:e000116; van Waning JI et al. J Am Coll Cardiol, 2018 Feb;71:711-722; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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 alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostCm	Uncertain	0.68
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.73		Gain of ubiquitination at K1848 (P = 0.0337);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.84

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: rs730880822; hg19: chr14-23884229; COSMIC: COSV62521001; COSMIC: COSV62521001;