Genetic Variant MYL3:p.Glu143Lys (chr3-46859529-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PS3PM1PP2PP3_ModeratePP5BS2

The NM_000258.3(MYL3):c.427G>A(p.Glu143Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000059674: "In vitro and in vivo functional studies, including transgenic mice expressing the p.Glu413Lys human variant that had clinical features of RCM, support an impact on protein function (Lossie 2012 PMID:22131351, Sahni 2015 PMID:25910212, Yuan 2017 PMID:28371863)"" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E143E) has been classified as Likely benign. The gene MYL3 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MYL3
NM_000258.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:3O:1

Conservation

PhyloP100: 7.91

Publications

21 publications found

Variant links:

Genes affected

MYL3 (HGNC:7584): (myosin light chain 3) MYL3 encodes myosin light chain 3, an alkali light chain also referred to in the literature as both the ventricular isoform and the slow skeletal muscle isoform. Mutations in MYL3 have been identified as a cause of mid-left ventricular chamber type hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]

MYL3 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 8
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYL3 links:

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ACMG classification

Specifications for MYL3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000059674: "In vitro and in vivo functional studies, including transgenic mice expressing the p.Glu413Lys human variant that had clinical features of RCM, support an impact on protein function (Lossie 2012 PMID: 22131351, Sahni 2015 PMID: 25910212, Yuan 2017 PMID: 28371863)"; SCV000254448: Experimental studies have shown that this missense change affects MYL3 function (PMID: 22131351).; SCV004843326: An experimental study has shown that this variant may reduce affinity for the cardiac myosin heavy chain in vitro (PMID: 22131351). In a transgenic mouse model, this variant caused a phenotype consistent with severe restrictive cardiomyopathy, including increased ventricular stiffness, sarcomere abnormalities, and interstitial cardiac fibrosis (PMID: 28371863).; SCV000319085: Functional studies suggest this alteration impacts a variety of mechanistic properties of myosin, and transgenic mice overexpressing E143K exhibit a phenotype consistent with restrictive cardiomyopathy; however, the clinical relevance of these results is unclear (Lossie J et al. Cardiovasc Res. 2012;93(3):390-6; Yuan CC et al. Cardiovasc Res. 2017;113(10):1124-1136; Wang Y et al. Open Biol. 2018;8(4):170240).; SCV001352584: An experimental study has shown that this variant may reduce affinity for the cardiac myosin heavy chain in vitro (PMID: 22131351). In a transgenic mouse model, this variant caused a phenotype consistent with severe restrictive cardiomyopathy, including increased ventricular stiffness, sarcomere abnormalities, and interstitial cardiac fibrosis (PMID: 28371863).; SCV001372376: Experimental evidence demonstrated the variant affects protein function (e.g. Lossie_2012, Sahni_2015).; SCV004114327: Functional studies suggested this variant reduces the binding affinity for the cardiac myosin heavy chain, and transgenic mice overexpressing the p.Glu413Lys variant exhibit clinical features of restrictive cardiomyopathy (Lossie J et al 2011. PubMed ID: 22131351; Sahni N et al 2015. PubMed ID: 25910212; Yuan CC et al 2017. PubMed ID: 28371863).

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000258.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.75572 (below the threshold of 3.09). Trascript score misZ: 1.3243 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 8, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

PP5

Variant 3-46859529-C-T is Pathogenic according to our data. Variant chr3-46859529-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14063.

BS2

High AC in GnomAdExome4 at 12 AD,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000258.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYL3	NM_000258.3	MANE Select	c.427G>A	p.Glu143Lys	missense	Exon 4 of 7	NP_000249.1	P08590
MYL3	NM_001406937.1		c.427G>A	p.Glu143Lys	missense	Exon 4 of 6	NP_001393866.1	P08590
MYL3	NM_001406938.1		c.427G>A	p.Glu143Lys	missense	Exon 6 of 9	NP_001393867.1	P08590

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYL3	ENST00000292327.6	TSL:1 MANE Select	c.427G>A	p.Glu143Lys	missense	Exon 4 of 7	ENSP00000292327.4	P08590
MYL3	ENST00000395869.5	TSL:1	c.427G>A	p.Glu143Lys	missense	Exon 4 of 6	ENSP00000379210.1	P08590
MYL3	ENST00000713934.1		c.559G>A	p.Glu187Lys	missense	Exon 4 of 7	ENSP00000519231.1	A0AAQ5BH63

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251486

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68054

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000986

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy (4)

Hypertrophic cardiomyopathy 8 (5)

Cardiomyopathy (2)

Cardiovascular phenotype (2)

not provided (2)

MYL3-related disorder (1)

not specified (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.3

PhyloP100

7.9

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.97

Vest4

0.87

MutPred

0.76

Gain of ubiquitination at E143 (P = 0.0258)

MVP

0.94

MPC

1.1

ClinPred

0.99

GERP RS

4.3

Varity_R

0.88

gMVP

0.85

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over