3-46859511-T-C

Variant names:

• chr3-46859511-T-C
• rs104893748
• NM_000258.3:c.445A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 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. M149I) has been classified as Likely pathogenic.

• 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
• Publications: 14 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 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, 0.881
• PP5: Variant 3-46859511-T-C is Pathogenic according to our data. Variant chr3-46859511-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3	c.445A>G	p.Met149Val	missense_variant	Exon 4 of 7	ENST00000292327.6	NP_000249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.445A>G	p.Met149Val	missense_variant	Exon 4 of 7	1	NM_000258.3	ENSP00000292327.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000530 Hom.: 0

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

Mar 18, 2012

Leiden Muscular Dystrophy (MYL3)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Nov 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Aug 31, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 149 of the MYL3 protein (p.Met149Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypertrophic cardiomyopathy (PMID: 8673105, 16267253). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14061). 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 tolerated. 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

Feb 13, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Benign	0.0	.;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Uncertain	2.9	M;M
PhyloP100		8.0
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
Vest4		0.96
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.74
gMVP		0.69
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893748; hg19: chr3-46901001;