rs199474707

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000258.3(MYL3):c.466G>T(p.Val156Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,860 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. V156M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYL3
NM_000258.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:6

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 9 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 chr3-46859490-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 3-46859490-C-A is Pathogenic according to our data. Variant chr3-46859490-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177841.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL3	NM_000258.3 linkuse as main transcript	c.466G>T	p.Val156Leu	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>T	p.Val156Leu	missense_variant	4/7	1	NM_000258.3	ENSP00000292327.4		P08590

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251364

Hom.:

AF XY:

0.0000147

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 8

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2017	A variant of uncertain significance has been identified in the MYL3 gene. The V156L (c.466 G>T) variant has been reported previously in association with HCM; however, clinical data was not provided and segregation studies were not performed (Walsh et al., 2017). Additionally, while a different nucleotide substitution (c.466 G>C) that also results in the V156L missense substitution and a missense variant in the same residue (V156M) were previously reported in association with HCM (Morita et al., 2006; Wang et al., 2014), the pathogenicity of these variants has not been definitively determined. Furthermore, the V156L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, the V156L (c.466 G>T) variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, missense variants in nearby residues (H155D, E152K) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 15, 2021	- -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 19, 2023

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Leu). This variant is present in population databases (rs199474707, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25132132, 25611685, 27532257, 31737537; Invitae). ClinVar contains an entry for this variant (Variation ID: 177841). 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.Val156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16754800, 23549607, 24111713, 27532257; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 30, 2018

The p.Val156Leu variant in MYL3 has been identified in 1 individual with HCM (LM M data). It has also been reported by other clinical laboratories in ClinVar (Va riation ID # 177841) and has been identified in 3/113668 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant (c.466G>C) resulting in the same amino acid change has been identified in 2 individuals with HCM (Wa ng 2014, Walsh 2017). In addition, another variant at this position (p.Val156Me t) has been identified in 2 individuals with increased left ventricular wall thi ckness and 5 individuals with HCM, one of whom with infantile-onset-disease (Mo rita 2006, Berge 2014, LMM data), suggesting that changes at this position may n ot be tolerated. Computational prediction tools and conservation analysis sugges t that this variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, the clinical significanc e of the p.Val156Leu variant is uncertain. ACMG/AMP Criteria applied: BP4, PS4_S upporting. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Uncertain

0.18

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.94

Sift

Benign

0.12

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.95

P;P

Vest4

0.84

MutPred

0.83

Loss of catalytic residue at V156 (P = 0.0505);Loss of catalytic residue at V156 (P = 0.0505);

MVP

0.95

MPC

0.79

ClinPred

0.91

GERP RS

4.3

Varity_R

0.66

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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