rs397516187

Positions:

• chr14-23419993-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_Moderate PM2 PP3 PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) variant has been identified in at least 9 individuals with DCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 1 individual with DCM and a bicuspid aortic valve (PS4_Moderate; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 5 affected relatives with DCM from 4 families (PP1_Moderate; LMM pers. comm.; OMGL pers. comm.). Additionally, this variant has also been reported in 1 individual with LVNC, 1 individual with non-ischemic cardiomyopathy and 1 individual with biventricular dilation with ventricular tachycardia (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013815/MONDO:0005021/002

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 7.65

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 7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.3578G>A	p.Arg1193His	missense_variant	27/40	ENST00000355349.4
MYH7	NM_001407004.1	c.3578G>A	p.Arg1193His	missense_variant	26/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.3578G>A	p.Arg1193His	missense_variant	27/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000844 AC: 2 AN: 236944 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129232

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: 0.00000957

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1447154 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 718534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000454

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2022	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1193 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 15769782), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 42965). This missense change has been observed in individuals with clinical features of dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 22464770, 27532257; Invitae; external communication). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397516187, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1193 of the MYH7 protein (p.Arg1193His). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 22, 2021	The NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) variant has been identified in at least 9 individuals with DCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 1 individual with DCM and a bicuspid aortic valve (PS4_Moderate; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 5 affected relatives with DCM from 4 families (PP1_Moderate; LMM pers. comm.; OMGL pers. comm.). Additionally, this variant has also been reported in 1 individual with LVNC, 1 individual with non-ischemic cardiomyopathy and 1 individual with biventricular dilation with ventricular tachycardia (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2, PP3. -

Primary familial dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 24, 2017

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

Variant summary: MYH7 c.3578G>A (p.Arg1193His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 236944 control chromosomes (gnomAD). c.3578G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy (Lakdawala_2012, Pugh_2014, Walsh_2017). These data indicate that the variant is 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: 22464770, 24503780, 27532257, 29300372). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified it as pathogenic, two (including a ClinGen expert panel) classified it as likely pathogenic, and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 01, 2021

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1193His variant in MYH7 has been identified in 7 Caucasian individuals with DCM and segregated with disease in 4 affected relatives, including one obligate carrier, and has been reported in one individual with HCM (Lakdawala 2012 PMID: 22464770, Walsh 2017 PMID: 27532257, LMM data). It has also been identified in 0.01% (1/104518) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A different variant (p.Arg1193Ser) at this position has been reported in 1 individual with DCM and segregated with disease in 3 affected family members (Villard 2005 PMID: 15769782), supporting that a change at this position may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP1, PP3. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2020

Reported in association with HCM and DCM (Lakdawala et al., 2012; Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (ClinVar Variant ID# 42965; SCV000564445.4; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29300372, 22464770, 27532257) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.67		Gain of catalytic residue at K1194 (P = 0.0127);
MVP		0.98
MPC		4.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.57
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: rs397516187; hg19: chr14-23889202; COSMIC: COSV62521743; COSMIC: COSV62521743;