3-46859490-C-T

Position:

chr3-46859490-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000258.3(MYL3):c.466G>A(p.Val156Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,062 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).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MYL3
NM_000258.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:9O:1

Conservation

PhyloP100: 7.91

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:

MYL3 (HGNC:):

MYL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 3-46859490-C-T is Pathogenic according to our data. Variant chr3-46859490-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31778.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, not_provided=1, Likely_pathogenic=5}. Variant chr3-46859490-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL3	NM_000258.3 linkuse as main transcript	c.466G>A	p.Val156Met	missense_variant	4/7	ENST00000292327.6	NP_000249.1	P08590A0A024R2Q5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6 linkuse as main transcript	c.466G>A	p.Val156Met	missense_variant	4/7	1	NM_000258.3	ENSP00000292327.4		P08590

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251364

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000852

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 10, 2018	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL3)	Mar 18, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2019	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with HCM (Berge 2014) and two FHS offspring, neither of whom had LVWT >13 mm, but one had left atrial enlargement and enhanced fractional shortening (Morita 2006). Clinvar: VUS (GeneDx, Invitae, CSER, Ambry, Montreal Heart Institute). Gnomad: 0.004% (1 AFR allele, 5 NFE alleles). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2024	Identified in several unrelated patients with HCM or other cardiac findings (PMID: 16754800, 23594557, 24111713, 25637381, 27532257, 23549607); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24111713, 16754800, 23594557, 27532257, 23549607, 35653365, 30665703, 37652022) -

Hypertrophic cardiomyopathy 8

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYL3 related disorder (PMID:16754800, PS1_P). A different missense change at the same codon has been reported to be associated with MYL3 related disorder (PMID:25132132, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.926, 3CNET: 0.975, 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: 0.000021, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 02, 2024	Criteria applied: PM5,PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3_Moderate+PS4_Moderate+PM5_Supporting -

Cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 17, 2022	This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23549607, 24111713, 27532257, 33495597) and in an individual showing early signs of left ventricular wall thickening (PMID 16754800). This variant has been identified in 6/282752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 21, 2023	- -

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Met). This variant is present in population databases (rs199474707, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 16754800, 23549607, 24111713, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 31778). 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.Met156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been observed in individuals with MYL3-related conditions (PMID: 25132132), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23549607, 24111713, 27532257, 33495597) and in an individual showing early signs of left ventricular wall thickening (PMID 16754800). This variant has been identified in 6/282752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The p.V156M variant (also known as c.466G>A), located in coding exon 4 of the MYL3 gene, results from a G to A substitution at nucleotide position 466. The valine at codon 156 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Oktay V et al. Anatol J Cardiol. 2023 Nov 1;27(11):628-638; external communication; Ambry internal data). 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. -

MYL3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2024

The MYL3 c.466G>A variant is predicted to result in the amino acid substitution p.Val156Met. This variant was reported in individuals with increased left ventricular wall thickness (Morita et al. 2006. PubMed ID: 16754800) and individuals with hypertrophic cardiomyopathy (Supplemental Table, Ho et al. 2013. PubMed ID: 23549607; Berge and Leren. 2014. PubMed ID: 24111713; Table S1B, Walsh et al. 2017. PubMed ID: 27532257). However, no functional studies were performed to support the pathogenicity of this variant. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the majority of laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/31778/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Increased left ventricular wall thickness

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Dec 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.92

MVP

0.98

MPC

0.90

ClinPred

0.94

GERP RS

4.3

Varity_R

0.83

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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