rs199474703

chr3-46860702-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000258.3(MYL3):c.281G>A(p.Arg94His) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R94C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 4.86

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 12 ACMG points.

• PM1: In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 36 pathogenic changes around while only 6 benign (86%) in NM_000258.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-46860702-C-T is Pathogenic according to our data. Variant chr3-46860702-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46860702-C-T is described in Lovd as [Pathogenic]. Variant chr3-46860702-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL3	NM_000258.3	c.281G>A	p.Arg94His	missense_variant	3/7	ENST00000292327.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL3	ENST00000292327.6	c.281G>A	p.Arg94His	missense_variant	3/7	1	NM_000258.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251298 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 28, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 31777). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18409188, 23283745, 26443374, 27532257, 29398688). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199474703, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the MYL3 protein (p.Arg94His). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 03, 2022	The p.Arg94His variant in MYL3 has been reported in at least 9 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 10 affected individuals across these families (Fokstuen 2008 PMID: 19409188, Zou 2013 PMID: 23283745, Nomura 2016 PMID: 26443374, Walsh 2017 PMID: 27532257, Teramoto 2018 PMID: 29398688, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 31777) and has been identified in 0.0009% (1/113678) of European and 0.0007% (1/134582) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PP1_Strong, PS4_Moderate, PM2_Supporting. -

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26443374, 18409188, 23283745, 27532257, 29398688, 27535533, 34638741) -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL3)	Mar 18, 2012	- -

Hypertrophic cardiomyopathy 8 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine

Aug 01, 2015

- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 23, 2017

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 26, 2021

Variant summary: MYL3 c.281G>A (p.Arg94His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes. c.281G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Fokstuen_2008, Zou_2013, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2023

The p.R94H variant (also known as c.281G>A), located in coding exon 3 of the MYL3 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated individuals with hypertrophic cardiomyopathy (HCM) and segregated with HCM in two families in which it appeared to arise from a common ancestor (Fokstuen S et al. Hum Mutat, 2008 Jun;29:879-85; Nomura A et al. J Cardiol, 2016 Feb;67:133-9; Walsh R et al. Genet Med, 2017 02;19:192-203). This variant has also been seen in individuals with HCM who had variants in other cardiomyopathy-related genes (Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Lopes LR et al. Amyloid, 2019 Dec;26:243-247). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	Benign	0.24
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Benign	-0.040
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.94	L;L
MutationTaster	Benign	0.84	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.065	B;B
Vest4		0.71
MutPred		0.53		Gain of methylation at K98 (P = 0.0588);Gain of methylation at K98 (P = 0.0588);
MVP		0.93
MPC		0.43
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.20
gMVP		0.23

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: rs199474703; hg19: chr3-46902192;