chr3-46858426-T-C

Position:

chr3-46858426-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000258.3(MYL3):c.517A>G(p.Met173Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M173T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MYL3
NM_000258.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 3.80

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:

MYL3 (HGNC:):

MYL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) 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 chr3-46858425-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL3	NM_000258.3 linkuse as main transcript	c.517A>G	p.Met173Val	missense_variant	5/7	ENST00000292327.6	NP_000249.1	P08590A0A024R2Q5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6 linkuse as main transcript	c.517A>G	p.Met173Val	missense_variant	5/7	1	NM_000258.3	ENSP00000292327.4		P08590

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251116

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2024	Variant summary: MYL3 c.517A>G (p.Met173Val) results in a conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.517A>G has been reported in the literature in individuals affected with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (examples: Morita_2008, Walsh_2017,Ho_2018, Lamounier_2022, Alimohamed_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Huang_2015). The following publications have been ascertained in the context of this evaluation (PMID: 33662488, 30297972, 26385864, 33642254, 18403758, 27532257). ClinVar contains an entry for this variant (Variation ID: 31779). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 24, 2012	Variant classified as Uncertain Significance - Favor Pathogenic. The Met173Val v ariant (MYL3) has been reported in the literature in one individual with early o nset HCM, segregated with disease in two affected relatives (including one oblig ate carrier), and was absent from 1360 control chromosomes (Morita 2008, LMM dat a). This variant has not been identified in large and broad European American an d African American populations by the NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS); this low frequency is consistent with a disease causing role but insufficient to establish this with confidence. Methionine (Met) at po sition 173 is highly conserved in mammals, however computational analyses (bioch emical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the normal function of the protein. Addi tional studies are needed to fully assess the clinical significance of this vari ant. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 20, 2024	This missense variant replaces methionine with valine at codon 173 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional study has shown that this variant may increase calcium sensitivity and affect function (PMID: 26385864). However, clinical significance of this finding is not clear. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33495596), in an individual affected with childhood-onset cardiac hypertrophy (PMID: 18403758), and in an individual affected with dilated cardiomyopathy (PMID: 33662488). This variant has been identified in 1/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the MYL3 protein (p.Met173Val). This variant is present in population databases (rs199474708, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 18403758, 27532257, 33662488). ClinVar contains an entry for this variant (Variation ID: 31779). 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. Experimental studies have shown that this missense change affects MYL3 function (PMID: 26385864). 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. -

not provided

Uncertain:1Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL3)	Mar 18, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26385864, 27532257, 28301460, 18403758, 33662488, 26582918) -

Hypertrophic cardiomyopathy 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 19, 2023

This missense variant replaces methionine with valine at codon 173 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional study has shown that this variant may increase calcium sensitivity and affect function (PMID: 26385864). However, clinical significance of this finding is not clear. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33495596), in an individual affected with childhood-onset cardiac hypertrophy (PMID: 18403758), and in an individual affected with dilated cardiomyopathy (PMID: 33662488). This variant has been identified in 1/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2021

The c.517A>G (p.M173V) alteration is located in exon 5 (coding exon 5) of the MYL3 gene. This alteration results from a A to G substitution at nucleotide position 517, causing the methionine (M) at amino acid position 173 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

CardioboostCm

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.46

T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.088

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

2.0

M;M

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.33

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0060

B;B

Vest4

0.57

MutPred

0.48

Loss of glycosylation at K171 (P = 0.0476);Loss of glycosylation at K171 (P = 0.0476);

MVP

0.99

MPC

0.68

ClinPred

0.42

GERP RS

3.8

Varity_R

0.45

gMVP

0.87

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