rs104893748

chr3-46859511-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000258.3(MYL3):c.445A>G(p.Met149Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M149T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 3-46859511-T-C is Pathogenic according to our data. Variant chr3-46859511-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46859511-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL3	NM_000258.3	c.445A>G	p.Met149Val	missense_variant	4/7	ENST00000292327.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL3	ENST00000292327.6	c.445A>G	p.Met149Val	missense_variant	4/7	1	NM_000258.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 8 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2005	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL3)	Mar 18, 2012	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2017

The Met149Val mutation in the MYL3 gene has been published in association with HCM (Poetter K et al., 1996; Arad M et al., 2005). Poetter et al. reported Met149Val to co-segregate with HCM in one family, and did not detect the mutation in 378 control chromosomes from healthy individuals. Six of the 13 family members with HCM had a phenotype involving mid left ventricular chamber (MVC) thickening apparent in a left ventriculogram (Poetter K et al., 1996). Additionally, this study performed in vitro motility assays and demonstrated that myosin from patients with the Met149Val mutation translocated actin filaments somewhat faster than the control myosin. Arad et al. reported the Met149Val mutation in a 23 year old individual with HCM, who presented with palpitations. Previous clinical evaluations in this individual's relatives identified apical HCM in 5 individuals, and typical asymmetrical hypertrophy of the anterior basal septum in 6 individuals. Two other individuals in the family were reported to have heart failure, and 3 others had sudden death. Although Met149Val results in a conservative amino acid replacement of one non-polar residue for another, the Met149 residue is highly conserved across species. Mutations affecting nearby codons (Glu143Lys, Gly152Lys, Arg154His) have been reported in association with HCM, further supporting the functional importance of this region of the protein. In silico analysis predicts this change to be probably damaging to the structure/function of the protein. Furthermore, Met149Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Of note, studies performed on transgenic rabbits harboring the Met149Val mutation in the MYL3 gene failed to recapitulate an HCM phenotype (James J et al., 2002). However, the authors acknowledged the association of Met149Val with HCM in humans and noted that the conflicting data may be due to the young age of the animals used. In summary, Met149Val in the MYL3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2021

This sequence change replaces methionine with valine at codon 149 of the MYL3 protein (p.Met149Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8673105, 16267253). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects MYL3 function (PMID: 22131351). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The p.M149V variant (also known as c.445A>G), located in coding exon 4 of the MYL3 gene, results from an A to G substitution at nucleotide position 445. The methionine at codon 149 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in individuals with hypertrophic cardiomyopathy (HCM) and was shown to segregate with disease in multiple affected relatives in a family (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Arad M et al. Circulation, 2005 Nov;112:2805-11; Walsh R et al. Genet. Med., 2017 02;19:192-203). Functional studies suggest this variant may impact protein function; however, additional evidence is needed to confirm this finding (Sanbe A et al. Circ Res, 2000 Aug;87:296-302; James J et al. J Mol Cell Cardiol, 2002 Jul;34:873-82; Lossie J et al. Cardiovasc. Res., 2012 Mar;93:390-6; Vemuri R et al. Proc Natl Acad Sci U S A, 1999 Feb;96:1048-53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.41	B;B
Vest4		0.96
MVP		0.95
MPC		0.52
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.74
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs104893748; hg19: chr3-46901001;