rs199474705

Variant names:

• chr3-46859502-C-T
• rs199474705
• NM_000258.3:c.454G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000258.3(MYL3):​c.454G>A​(p.Glu152Lys) 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. 13/23 in silico tools predict a damaging 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. E152D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.91
• Publications: 4 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 10 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000258.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.959
• PP5: Variant 3-46859502-C-T is Pathogenic according to our data. Variant chr3-46859502-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31782.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3	c.454G>A	p.Glu152Lys	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.454G>A	p.Glu152Lys	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: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Other:1

Aug 09, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E152K likely pathogenic variant in the MYL3 gene has been reported previously in one individual with pre-adolescent HCM, and was absent in 400 control alleles (Kaski et al., 2009). Furthermore, the E152K variant 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. In addition, the E152K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Located in the calcium binding EF-hand domain, this substitution occurs at a position that is conserved across species (Kaski et al., 2009). Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, missense variants in nearby residues (M149V, M149T, M149I, R154C, R154H) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required. -

Mar 18, 2012

Leiden Muscular Dystrophy (MYL3)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Hypertrophic cardiomyopathy Uncertain:1

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 31782). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20031618, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 152 of the MYL3 protein (p.Glu152Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.1	H;H
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.83		Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.95
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199474705; hg19: chr3-46900992;