NM_000257.4:c.4472_4473delCCinsGT

Variant names:

• chr14-23417199-GG-AC
• NM_000257.4:c.4472_4473delCCinsGT
• MYH7 p.Ser1491Cys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PP2

The NM_000257.4(MYH7):c.4472_4473delCCinsGT (p.Ser1491Cys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.79). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S1491C: Benign (ClinVar VariationId 43020, 3 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.79
• 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 1S

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

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

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

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

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

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• 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, G2P
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 4 pathogenic, 0 benign (OR vs. background: 45.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 6.806). ClinVar shows strong pathogenic missense enrichment: 622 P/LP and 50 B/LB missense entries (ratio 12.4×).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH7 NM_000257.4	MANE Select	c.4472_4473delCCinsGT p.Ser1491Cys	missense	N/A	Prot: NP_000248.2 UniProt:
	MYH7 NM_001407004.1		c.4472_4473delCCinsGT p.Ser1491Cys	missense	N/A	Prot: NP_001393933.1 UniProt:
	MHRT NR_126491.1		n.652-13_652-12delGGinsAC	intron	Intron 4 of 5	Prot:

MYH7 NM_000257.4

MANE Select

HGVSc / HGVSpc.4472_4473delCCinsGTp.Ser1491Cys

Exon rankN/A

missense

Prot: NP_000248.2UniProt: P12883

MYH7 NM_001407004.1

HGVSc / HGVSpc.4472_4473delCCinsGTp.Ser1491Cys

Exon rankN/A

missense

Prot: NP_001393933.1UniProt: P12883

MHRT NR_126491.1

HGVSc / HGVSpn.652-13_652-12delGGinsAC

Exon rankIntron 4 of 5

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH7 ENST00000355349.4	TSL:1MANE Select	c.4472_4473delCCinsGT p.Ser1491Cys	missense	N/A	Prot: ENSP00000347507.3 UniProt:
	MYH7 ENST00000858540.1		c.4472_4473delCCinsGT p.Ser1491Cys	missense	N/A	Prot: ENSP00000528599.1 UniProt:
	MYH7 ENST00000965955.1		c.4472_4473delCCinsGT p.Ser1491Cys	missense	N/A	Prot: ENSP00000636014.1 UniProt:

MYH7 ENST00000355349.4

TSL:1MANE Select

HGVSc / HGVSpc.4472_4473delCCinsGTp.Ser1491Cys

Exon rankN/A

missense

Prot: ENSP00000347507.3UniProt: P12883

MYH7 ENST00000858540.1

HGVSc / HGVSpc.4472_4473delCCinsGTp.Ser1491Cys

Exon rankN/A

missense

Prot: ENSP00000528599.1UniProt: A0ACI8PLM0

MYH7 ENST00000965955.1

HGVSc / HGVSpc.4472_4473delCCinsGTp.Ser1491Cys

Exon rankN/A

missense

Prot: ENSP00000636014.1UniProt: A0ACI8PLM0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr14-23886408;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar