rs727505026

chr14-23419958-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):c.3613G>A(p.Glu1205Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,892 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. E1205G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 5.95

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 14-23419958-C-T is Pathogenic according to our data. Variant chr14-23419958-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179656.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=5, Likely_pathogenic=1}. Variant chr14-23419958-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.3613G>A	p.Glu1205Lys	missense_variant	27/40	ENST00000355349.4
MYH7	NM_001407004.1	c.3613G>A	p.Glu1205Lys	missense_variant	26/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.3613G>A	p.Glu1205Lys	missense_variant	27/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249722 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135100

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455892 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 723552

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy;C0013404:Dyspnea Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 28, 2014

- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1205 of the MYH7 protein (p.Glu1205Lys). This variant is present in population databases (rs727505026, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18258667, 24111713, 26914223, 31737537, 34542152; Invitae). ClinVar contains an entry for this variant (Variation ID: 179656). 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%. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 04, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The Glu1205Lys variant in MYH7 has been reported in 1 individual with HCM (Waldmuller 2008) and was absent large population studies (NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS/). This variant was predicted to be pathogenic using a co mputational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Although th is data supports that the Glu1205Lys variant may be pathogenic, additional studi es are needed to fully assess its clinical significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 12, 2023

This missense variant replaces glutamic acid with lysine at codon 1205 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18258667, 24111713, 28771489, 26914223, 2793070, 28771489, 35200695). It has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 33552729, 36788754) and in an individual affected with sudden unexplained death (PMID: 27930701). This variant has been identified in 1/249722 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

Sep 13, 2023

The p.E1205K variant (also known as c.3613G>A), located in coding exon 25 of the MYH7 gene, results from a G to A substitution at nucleotide position 3613. The glutamic acid at codon 1205 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals from hypertrophic cardiomyopathy (HCM) cohorts, individuals submitted for HCM genetic testing, and individuals indicated has having HCM on review of electronic health record (Waldmüller S et al. Clin Chem, 2008 Apr;54:682-7; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Park J et al. Hum Mol Genet. 2022 Mar;31(5):827-837). This variant has also been detected in an individual reported to have dilated cardiomyopathy and a sudden unexplained death case (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Guelly C et al. PeerJ. 2021 Jan;9:e10711). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

MYH7-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The MYH7 c.3613G>A variant is predicted to result in the amino acid substitution p.Glu1205Lys. This variant has been reported in at least three individuals with hypertrophic cardiomyopathy, an individual with dilated cardiomyopathy and a case of sudden unexplained death (Table 2, Waldmuller et al. 2008. PubMed ID: 18258667; Table S2, Murphy et al. 2016. PubMed ID: 26914223; Table S6, Park et al. 2022. PubMed ID: 34542152; Table 2, Sanchez et al. 2016. PubMed ID: 27930701; Table S2, Guelly et al. 2021. PubMed ID: 33552729). It has been reported in an arrhythmogenic disorders study; However, no clinical details were provided (Marschall et al. 2019. PubMed ID: 31737537). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

May 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.63		Gain of MoRF binding (P = 9e-04);
MVP		0.98
MPC		3.6
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.57
gMVP		0.94

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: rs727505026; hg19: chr14-23889167;