rs886039204

chr14-23423966-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000257.4(MYH7):c.2863G>A(p.Asp955Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,888 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). Synonymous variant affecting the same amino acid position (i.e. D955D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 7.74

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 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2863G>A	p.Asp955Asn	missense_variant	23/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2863G>A	p.Asp955Asn	missense_variant	22/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2863G>A	p.Asp955Asn	missense_variant	23/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135920

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: 0.00000274 AC: 4 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2022	Identified in patients with cardiomyopathy in published literature; however, all probands were found to harbor other variants in MYH7 or another cardiomyopathy-associated gene (Hoedemaekers et al., 2007; vanSpaendonck-Zwarts et al., 2013; Petropoulou et al., 2017; van Waning et al., 2018); 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: 17947214, 23349452, 29447731, 28642161, 25332820, 20952769, 30650640, 20965760) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 14, 2023	PM2_supporting -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2022

The p.D955N variant (also known as c.2863G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2863. The aspartic acid at codon 955 is replaced by asparagine, an amino acid with highly similar properties. This variant along with MYH7 p.D545N in cis reportedly co-segregated with disease in families with dilated cardiomyopathy (DCM) and left ventricular non-compaction (Hoedemaekers YM et al. Eur Heart J. 2007;28(22):2732-7; van den Berg MP et al. Eur J Heart Fail. 2010;12(12):1297-9). Both p.D545N and p.D955N were detected in another LVNC cohort; however, additional details were limited (Chang B. Mol Genet Metab. 2011 Feb;102(2):200-6). This alteration also segregated with the TNNT2 p.N83H variant in multiple members of a consanguineous family with DCM; individuals with either variant alone were unaffected (Petropoulou E et al. Eur J Med Genet, 2017 Sep;60:485-488). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic when in cis with MYH7 p.D545N; however, the clinical significance of the p.D955N variant alone is unclear. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 10, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 955 of the MYH7 protein (p.Asp955Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with left ventricular noncompaction or dilated cardiomyopathy (PMID: 20965760, 23349452, 29447731). ClinVar contains an entry for this variant (Variation ID: 264608). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.72		Loss of stability (P = 0.0348);
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.95

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: rs886039204; hg19: chr14-23893175; COSMIC: COSV62522274;