NM_000257.4:c.3301G>A

Variant names:

• chr14-23420993-C-T
• rs367546859
• NM_000257.4:c.3301G>A
• MYH7 p.Gly1101Ser

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 (ACMG Germline Pathogenicity v2019). PM2_SupportingPP2

The NM_000257.4(MYH7):c.3301G>A (p.Gly1101Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000403 (AC=65) in the gnomAD database across 1,612,386 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000389. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). 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)

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 2.20
• Publications: 12 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 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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000389 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	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.3301G>A p.Gly1101Ser	missense	Exon 26 of 40	Prot: NP_000248.2 UniProt:
	MYH7 NM_001407004.1		c.3301G>A p.Gly1101Ser	missense	Exon 25 of 39	Prot: NP_001393933.1 UniProt:

MYH7 NM_000257.4

MANE Select

HGVSc / HGVSpc.3301G>Ap.Gly1101Ser

Exon rankExon 26 of 40

missense

Prot: NP_000248.2UniProt: P12883

MYH7 NM_001407004.1

HGVSc / HGVSpc.3301G>Ap.Gly1101Ser

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>A p.Gly1101Ser	missense	Exon 26 of 40	Prot: ENSP00000347507.3 UniProt:
	MYH7 ENST00000858540.1		c.3301G>A p.Gly1101Ser	missense	Exon 26 of 40	Prot: ENSP00000528599.1 UniProt:
	MYH7 ENST00000965955.1		c.3301G>A p.Gly1101Ser	missense	Exon 26 of 40	Prot: ENSP00000636014.1 UniProt:

MYH7 ENST00000355349.4

TSL:1MANE Select

HGVSc / HGVSpc.3301G>Ap.Gly1101Ser

Exon rankExon 26 of 40

missense

Prot: ENSP00000347507.3UniProt: P12883

MYH7 ENST00000858540.1

HGVSc / HGVSpc.3301G>Ap.Gly1101Ser

Exon rankExon 26 of 40

missense

Prot: ENSP00000528599.1UniProt: A0ACI8PLM0

MYH7 ENST00000965955.1

HGVSc / HGVSpc.3301G>Ap.Gly1101Ser

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152148	Cov:32
GnomAD2 exomes	AF: 0.0000597	AC:15	Hom:	AN:251430	Cov:
GnomAD4 exome	AF: 0.0000425	AC:62	Hom:0	AN:1460238	Cov:31
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152148	Cov:32
TOPMed (Bravo)	AF: 0.0000529	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000112	AC:26	Hom:0	AN:232942	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000312 *	3	9622	0.000288 *	3	10428
BipEx(Bipolar disorder (including schizoaffective))	0.000141	4	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.000143	6	41958	0.0000897	6	66886
SCHEMA(Schizophrenia)	0.0000659	8	121480	0.0000421	8	189996

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiomyopathy (2)
-	2	-	not provided (2)
-	2	-	not specified (2)
-	2	-	Primary familial hypertrophic cardiomyopathy (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
CardioboostCm	Benign	0.0023
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.35	N
FuncVEP CTI	Benign	0.0043
GPN-Star LLR	N/A	-3.3
GPN-Star score	N/A	3.3
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.84	T
Mutation Taster	N/A	27/73	disease causing
MutationAssessor	Benign	0.25	N
PhyloP100	Benign	2.2
popEVE	Benign	-2.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Benign	0.52	T
Sift4G	Benign	0.74	T
Varity_R	N/A	0.20
VESM-3B	Benign	-4.6

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;

COSMIC: COSV62517001;

COSMIC: COSV62517001;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar