rs199474706

chr3-46859493-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000258.3(MYL3):c.463C>G(p.His155Asp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H155L) 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:2 U:1 O:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 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 chr3-46859493-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 3-46859493-G-C is Pathogenic according to our data. Variant chr3-46859493-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31783.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1, Pathogenic=1}. Variant chr3-46859493-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL3	NM_000258.3	c.463C>G	p.His155Asp	missense_variant	4/7	ENST00000292327.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL3	ENST00000292327.6	c.463C>G	p.His155Asp	missense_variant	4/7	1	NM_000258.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2023	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 155 of the MYL3 protein (p.His155Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20031618, 27532257, 28790153). ClinVar contains an entry for this variant (Variation ID: 31783). 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. 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. -
Likely pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jul 25, 2018	The MYL3 His155Asp variant has been reported previously in a childhood HCM case (Kaski JP, et al., 2009). It has also been identified in 1 additional HCM patient (due to overlap with the Kaski JP, et al., 2009) by the Oxford Medical Genetics Laboratory (Walsh R, et al., 2017), in both families the variant segregated with multiple affected family members (Pers. Comm.). The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband and the variant cosegregated to the proband's affected sibling. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. In summary, using the adapted ACMG criteria (Kelly MA, et al., 2018), the variant has been found to segregate strongly in at least 2 families (PP1_strong), is rare in the general population databases (PM2), in silico tools predict the variant to be deleterious (PP3) and it has been reported in a total of 3 probands (PS4_supporting), therefore we classify MYL3 His155Asp as "likely pathogenic". -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2013	The His155Asp mutation in the MYL3 gene has been reported in one preadolescent child with HCM and it was absent from 200 control individuals (Kaski J et al., 2009). His155Asp results in a non-conservative amino acid substitution of a negatively charged Aspartic acid with a positively charged Histidine at a position that is conserved across species. Mutations in nearby residues (Glu152Lys, Arg154Cys, Arg154His) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, His155Asp 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 summary, His155Asp in the MYL3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL3)	Mar 18, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.72		Gain of disorder (P = 0.0857);Gain of disorder (P = 0.0857);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.96
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs199474706; hg19: chr3-46900983;