rs199474703
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_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
NM_000258.3 missense
Scores
1
11
8
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 genomes
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32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135848
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461766Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727196
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GnomAD4 genome Cov.: 32
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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). - |
not provided Pathogenic:1Other: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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
.;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Gain of methylation at K98 (P = 0.0588);Gain of methylation at K98 (P = 0.0588);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at