rs730880859

Variant names:

• chr14-23430595-A-T
• rs730880859
• NM_000257.4:c.964T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS4_Supporting PM2 PM1

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.964T>A (p.Ser322Thr) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA017009/MONDO:0005045/002

• 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:1 U:2
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.964T>A	p.Ser322Thr	missense_variant	Exon 11 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.964T>A	p.Ser322Thr	missense_variant	Exon 10 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.964T>A	p.Ser322Thr	missense_variant	Exon 11 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.964T>A	p.Ser322Thr	missense_variant	Exon 11 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.964T>A	p.Ser322Thr	missense_variant	Exon 10 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461774 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Apr 21, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000257.4(MYH7):c.964T>A (p.Ser322Thr) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1. -

Oct 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This sequence change replaces serine with threonine at codon 322 of the MYH7 protein (p.Ser322Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181330). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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. -

not provided Pathogenic:1

Sep 27, 2012

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser322Thr (TCC>ACC):c.964 T>A in exon 11 of the MYH7 gene (NM_000257.2). The Ser322Thr variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser322Thr results in a conservative amino acid substitution of one neutral, polar residue for another at a position that is conserved through mammals. A mutation affecting the same residue (Ser322Phe), as well as mutations in nearby residues (Val320Met, Ala326Pro) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ser322Thr was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Ser322Thr 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 HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
CardioboostCm	Uncertain	0.49
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.035	D
Polyphen		0.0	B
Vest4		0.56
MutPred		0.49		Gain of catalytic residue at E317 (P = 0.0086);
MVP		0.88
MPC		1.8
ClinPred		0.78	D
GERP RS		3.4
Varity_R		0.54
gMVP		0.68
Mutation Taster		=67/33	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730880859; hg19: chr14-23899804;