rs202141423

Positions:

chr3-46859510-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

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. M149V) has been classified as 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:2

Conservation

PhyloP100: 9.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) 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 chr3-46859511-T-C is described in Lovd as [Pathogenic].

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 id is 43123.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL3	NM_000258.3 linkuse as main transcript	c.446T>C	p.Met149Thr	missense_variant	4/7	ENST00000292327.6	NP_000249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6 linkuse as main transcript	c.446T>C	p.Met149Thr	missense_variant	4/7	1	NM_000258.3	ENSP00000292327	P1

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251474

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

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 SAS 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:

0.00000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 8

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2024

The p.M149T variant (also known as c.446T>C), located in coding exon 4 of the MYL3 gene, results from a T to C substitution at nucleotide position 446. The methionine at codon 149 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Olfson E et al. PLoS One, 2015 Sep;10:e0135193; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Harper AR et al. Nat Genet, 2021 Feb;53:135-142; external communications; Ambry internal data). Another variant at the same codon, p.M149V (c.445A>G), has been detected in individuals with HCM and reported to segregate with disease in multiple affected family members (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Arad M et al. Circulation, 2005 Nov;112:2805-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 13, 2014

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. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

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; Invitae). 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 v4.3

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

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;D

Eigen

Benign

0.037

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.67

Sift

Benign

0.038

D;D

Sift4G

Benign

0.85

T;T

Polyphen

0.18

B;B

Vest4

0.99

MVP

0.94

MPC

1.0

ClinPred

0.99

GERP RS

4.3

Varity_R

0.84

gMVP

0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over