dbSNP rs202141423: MYL3:p.Met149Thr (chr3-46859510-A-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5

The NM_000258.3(MYL3):c.446T>C(p.Met149Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M149I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYL3
NM_000258.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 9.32

Publications

1 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: PanelApp Australia, 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000258.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-46859509-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180442.

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, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy 8.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

PP5

Variant 3-46859510-A-G is Pathogenic according to our data. Variant chr3-46859510-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43123.

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
MYL3	NM_000258.3	MANE Select	c.446T>C	p.Met149Thr	missense	Exon 4 of 7	NP_000249.1
MYL3	NM_001406937.1		c.446T>C	p.Met149Thr	missense	Exon 4 of 6	NP_001393866.1
MYL3	NM_001406938.1		c.446T>C	p.Met149Thr	missense	Exon 6 of 9	NP_001393867.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYL3	ENST00000292327.6	TSL:1 MANE Select	c.446T>C	p.Met149Thr	missense	Exon 4 of 7	ENSP00000292327.4
MYL3	ENST00000395869.5	TSL:1	c.446T>C	p.Met149Thr	missense	Exon 4 of 6	ENSP00000379210.1
MYL3	ENST00000713934.1		c.578T>C	p.Met193Thr	missense	Exon 4 of 7	ENSP00000519231.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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:

0.00000398

AC:

AN:

251474

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74458

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 8

Pathogenic:1Uncertain:1

Jan 03, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014061,VCV000181444, PMID:8673105,25132132, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.671, 3CNET: 0.928, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYL3 related disorder (PMID:23283745, PS1_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

May 20, 2025

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:2

Jun 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYL3 c.446T>C (p.Met149Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-06 in 251474 control chromosomes (gnomAD). c.446T>C has been observed in individuals affected with Hypertrophic Cardiomyopathy (Zou_2013, Walsh_2017, McGurk_2023, internal data). These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as likely pathogenic by our lab (c.445A>G, p.Met149Val), supporting the critical relevance of codon 149 to MYL3 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26332594, 27532257, 23283745). ClinVar contains an entry for this variant (Variation ID: 43123). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Aug 13, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Met149Thr variant in MYL3 has been reported in 1 Asian individual with HCM ( Zou 2013) and has been identified by our laboratory in 1 Asian adult with HCM, b ut has also been identified in 1/200 of Southern Han Chinese chromosomes by the 1000 Genomes Project (dbSNP rs202141423). Another pathogenic variant at the same position has been reported (Met149Val; Poetter 1996, Arad 2005) suggesting a ch ange at this residue may not be tolerated. Computational prediction tools and co nservation analysis do not provide strong support for or against an impact to th e protein. In summary, the clinical significance of the Met149Thr variant is unc ertain.

Cardiovascular phenotype

Pathogenic:1

Jul 01, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.446T>C (p.M149T) alteration is located in exon 4 (coding exon 4) of the MYL3 gene. This alteration results from a T to C substitution at nucleotide position 446, causing the methionine (M) at amino acid position 149 to be replaced by a threonine (T). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Zou, 2013; Olfson, 2015; Walsh, 2017; Harper, 2021; external communications; Ambry internal data). Another variant at the same codon, c.445A>G (p.M149V), has been detected in individuals with HCM and reported to segregate with disease in multiple affected family members (Poetter, 1996; Arad, 2005). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Hypertrophic cardiomyopathy

Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 149 of the MYL3 protein (p.Met149Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 27532257, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 43123). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Met149 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8673105, 16267253, 22131351). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

CardioboostCm

Uncertain

0.89

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

Eigen

Benign

0.037

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.9

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.67

Sift

Benign

0.038

Sift4G

Benign

0.85

Polyphen

0.18

Vest4

0.99

MVP

0.94

MPC

1.0

ClinPred

0.99

GERP RS

4.3

Varity_R

0.84

gMVP

0.69

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over