chr14-23420993-C-G

Variant names:

• chr14-23420993-C-G
• rs367546859
• NM_000257.4:c.3301G>C
• MYH7 p.Gly1101Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO8_Supporting

The NM_000257.4(MYH7):c.3301G>C (p.Gly1101Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000548 (AC=8) in the gnomAD database across 1,460,240 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000262. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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.G1101= (synonymous): Likely_benign (ClinVar VariationId 1331824, 1 star); p.G1101S: Uncertain_significance (ClinVar VariationId 161325, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• Publications: 3 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

ENSG00000294572 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000003 — very rare (O3 supporting [+1])
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 6.81 (threshold ≥3.09 for constraint)

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.3301G>C p.Gly1101Arg	missense	Exon 26 of 40	Prot: NP_000248.2 UniProt:
	MYH7 NM_001407004.1		c.3301G>C p.Gly1101Arg	missense	Exon 25 of 39	Prot: NP_001393933.1 UniProt:

MYH7 NM_000257.4

MANE Select

HGVSc / HGVSpc.3301G>Cp.Gly1101Arg

Exon rankExon 26 of 40

missense

Prot: NP_000248.2UniProt: P12883

MYH7 NM_001407004.1

HGVSc / HGVSpc.3301G>Cp.Gly1101Arg

Exon rankExon 25 of 39

missense

Prot: NP_001393933.1UniProt: P12883

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH7 ENST00000355349.4	TSL:1MANE Select	c.3301G>C p.Gly1101Arg	missense	Exon 26 of 40	Prot: ENSP00000347507.3 UniProt:
	MYH7 ENST00000858540.1		c.3301G>C p.Gly1101Arg	missense	Exon 26 of 40	Prot: ENSP00000528599.1 UniProt:
	MYH7 ENST00000965955.1		c.3301G>C p.Gly1101Arg	missense	Exon 26 of 40	Prot: ENSP00000636014.1 UniProt:

MYH7 ENST00000355349.4

TSL:1MANE Select

HGVSc / HGVSpc.3301G>Cp.Gly1101Arg

Exon rankExon 26 of 40

missense

Prot: ENSP00000347507.3UniProt: P12883

MYH7 ENST00000858540.1

HGVSc / HGVSpc.3301G>Cp.Gly1101Arg

Exon rankExon 26 of 40

missense

Prot: ENSP00000528599.1UniProt: A0ACI8PLM0

MYH7 ENST00000965955.1

HGVSc / HGVSpc.3301G>Cp.Gly1101Arg

Exon rankExon 26 of 40

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000548	AC:8	Hom:0	AN:1460240	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	67854	0.00000751	1	133226

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
CardioboostCm	Benign	0.0029
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.030
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.49	N
FuncVEP CTI	Benign	0.12
GPN-Star LLR	N/A	-7.7
GPN-Star score	N/A	7.7
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.23	T
Mutation Taster	N/A	53/47	polymorphism
MutationAssessor	Benign	1.7	L
PhyloP100	Benign	2.2
popEVE	Benign	-2.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.40
Sift	Benign	0.030	D
Sift4G	Benign	0.54	T
Varity_R	N/A	0.35
VESM-3B	Benign	-8.5

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs367546859;

hg19: chr14-23890202;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar