Variant chr3-46860702-C-T details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 4.86

Variant links:

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 links:

Genome browser will be placed here

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 linkuse as main transcript	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 linkuse as main transcript	c.281G>A	p.Arg94His	missense_variant	3/7	1	NM_000258.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251298

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135848

show subpopulations

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:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727196

show subpopulations

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.:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

CardioboostCm

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Benign

-0.040

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.92

.;D

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.94

L;L

MutationTaster

Benign

0.84

D;D

PrimateAI

Uncertain

0.56

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over