rs121913631

Variant names:

• chr14-23424107-G-C
• rs121913631
• NM_000257.4:c.2722C>G
• MYH7 p.Leu908Val

Your query was ambiguous. Multiple possible variants found:

• chr14-23424107-G-C
• chr14-23424107-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 21 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000257.4(MYH7):c.2722C>G (p.Leu908Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000372 (AC=6) in the gnomAD database across 1,614,104 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000692499: "In vitro assays suggest that the variant may impact myosin cross-bridge kinetics (Palmiter et al., 2000) and increase the velocity by which myosin translocated actin (Alpert NR, et al., 2005)."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.L908M: Likely_pathogenic (ClinVar VariationId 2763277, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L908= (synonymous): Likely_benign (ClinVar VariationId 763750, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 2.98
• Publications: 25 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

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: Pathogenic. The variant received 21 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000692499: "In vitro assays suggest that the variant may impact myosin cross-bridge kinetics (Palmiter et al., 2000) and increase the velocity by which myosin translocated actin (Alpert NR, et al., 2005)."; SCV000917841: The rate of translocation of acting filaments as measured by in-vitro motility assays was 35% of wild-type levels (Cuda_1993). Subsequently, a gain of function effect was observed as an increase in actin filament velocity in the in-vitro motility assay (Palmiter_2000) and an increase in actin sliding velocity (Alpert_2005).; SCV000208505: Published functional studies demonstrated L908V increases the velocity of actin filament movement in the in vitro motility assays performed using cardiac or skeletal muscle tissue from L908V heterozygous individuals (Palmiter et al., 2000; Alpert et al., 2005).; SCV000280334: "There is functional data available: Cuda et al. (1993, 1997) took skeletal muscle biopsies from HCM patients with this variant, and showed that the mutant cardiac myosin is also present in skeletal muscle and has abnormal function in an in vitro assay in which actin filaments are translocated by myosin bound to a coverslip surface." Cuda et al. (1993, 1997); SCV000319946: "In vitro motility assays showed an increase in actin filament velocities and gain of function (Palmiter KA et al. J Muscle Res Cell Motil. 2000;21(7):609-20; Alpert NR et al. Am J Physiol Heart Circ Physiol. 2005;288(3):H1097-102)."; SCV000059471: studies have shown that this variant may impact protein function (Cuda 1993, Alpert 2005).; SCV000546238: Experimental studies have shown that this missense change affects MYH7 function (PMID: 8483915, 9172070, 11227787, 15528230).; SCV004844781: An in vitro motility assay has shown that the mutant protein exhibits enhanced mechanical performance at the single molecule level (PMID: 11227787).; SCV001341816: An in vitro motility assay has shown that the mutant protein exhibits enhanced mechanical performance at the single molecule level (PMID: 11227787).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 106 pathogenic, 0 benign rare missense variants (OR vs. background: 1065.0).; ±8 AA neighbourhood: 20 pathogenic, 0 benign (OR vs. background: 205.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000488 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.L908M: Likely_pathogenic (ClinVar VariationId 2763277, 1 star); Other variants at the same amino acid residue (not pathogenic): p.L908= (synonymous): Likely_benign (ClinVar VariationId 763750, 1 star)
	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×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (17/17 total P/LP).

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.2722C>G p.Leu908Val	missense	Exon 23 of 40	Prot: NP_000248.2 UniProt:
	MYH7 NM_001407004.1		c.2722C>G p.Leu908Val	missense	Exon 22 of 39	Prot: NP_001393933.1 UniProt:

MYH7 NM_000257.4

MANE Select

HGVSc / HGVSpc.2722C>Gp.Leu908Val

Exon rankExon 23 of 40

missense

Prot: NP_000248.2UniProt: P12883

MYH7 NM_001407004.1

HGVSc / HGVSpc.2722C>Gp.Leu908Val

Exon rankExon 22 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.2722C>G p.Leu908Val	missense	Exon 23 of 40	Prot: ENSP00000347507.3 UniProt:
	MYH7 ENST00000858540.1		c.2722C>G p.Leu908Val	missense	Exon 23 of 40	Prot: ENSP00000528599.1 UniProt:
	MYH7 ENST00000965955.1		c.2722C>G p.Leu908Val	missense	Exon 23 of 40	Prot: ENSP00000636014.1 UniProt:

MYH7 ENST00000355349.4

TSL:1MANE Select

HGVSc / HGVSpc.2722C>Gp.Leu908Val

Exon rankExon 23 of 40

missense

Prot: ENSP00000347507.3UniProt: P12883

MYH7 ENST00000858540.1

HGVSc / HGVSpc.2722C>Gp.Leu908Val

Exon rankExon 23 of 40

missense

Prot: ENSP00000528599.1UniProt: A0ACI8PLM0

MYH7 ENST00000965955.1

HGVSc / HGVSpc.2722C>Gp.Leu908Val

Exon rankExon 23 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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152222	Cov:32
GnomAD4 exome	AF: 0.00000274	AC:4	Hom:0	AN:1461882	Cov:34
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152222	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000523	AC:2	Hom:0	AN:38206	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Hypertrophic cardiomyopathy (4)
4	-	-	not provided (4)
3	-	-	Hypertrophic cardiomyopathy 1 (3)
2	-	-	Cardiomyopathy (2)
2	-	-	Cardiovascular phenotype (2)
2	-	-	Primary familial hypertrophic cardiomyopathy (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
CardioboostCm	Pathogenic	1.0
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Pathogenic	0.93
GPN-Star LLR	N/A	-9.0
GPN-Star score	N/A	9.0
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	2/98	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.5	H
PhyloP100	Benign	3.0
popEVE	Benign	-3.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.54
VESM-3B	Benign	-10

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
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: rs121913631;

hg19: chr14-23893316;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar