dbSNP rs150634297: MYL3:p.Val79Ile (chr3-46860748-C-T) – ACMG Classification: Uncertain_significance (4 pts)

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain EF-hand 1 (size 37) in uniprot entity MYL3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000258.3

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3 link	c.235G>A	p.Val79Ile	missense_variant	Exon 3 of 7	ENST00000292327.6	NP_000249.1	P08590A0A024R2Q5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6 link	c.235G>A	p.Val79Ile	missense_variant	Exon 3 of 7	1	NM_000258.3	ENSP00000292327.4		P08590

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152168

Hom.:

0

Cov.:

32

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

7

AN:

251470

Hom.:

0

AF XY:

0.0000221

AC XY:

3

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461874

Hom.:

0

Cov.:

33

AF XY:

0.0000633

AC XY:

46

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000917

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152286

Hom.:

0

Cov.:

32

AF XY:

0.0000134

AC XY:

1

AN XY:

74472

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000663

Hom.:

0

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

1

ALSPAC

AF:

0.000519

AC:

2

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.0000330

AC:

4

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Jan 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with isoleucine at codon 79 of the MYL3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with a mild form of late-onset hypertrophic cardiomyopathy (PMID: 22957257). However, three carrier individuals from this family had electrocardiogram and/or echocardiographic abnormalities that did not fulfill diagnostic criteria for hypertrophic cardiomyopathy. In addition, five carrier individuals from this family showed an unaffected phenotype. This variant has been identified in 7/251470 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. -

Nov 24, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:2

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with isoleucine at codon 79 of the MYL3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with a mild form of late-onset hypertrophic cardiomyopathy (PMID: 22957257). However, three carrier individuals from this family had electrocardiogram and/or echocardiographic abnormalities that did not fulfill diagnostic criteria for hypertrophic cardiomyopathy. In addition, five carrier individuals from this family showed an unaffected phenotype. This variant has been identified in 7/251470 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 79 of the MYL3 protein (p.Val79Ile). This variant is present in population databases (rs150634297, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22957257). ClinVar contains an entry for this variant (Variation ID: 161329). 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. 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. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified

Uncertain:1

Feb 14, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYL3 c.235G>A (p.Val79Ile) results in a conservative amino acid change in 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 2.8e-05 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.235G>A has been reported in the literature as segregating with disease in at least one family, in which one heterozygous individual was diagnosed with asymptomatic hypertrophic cardiomyopathy (HCM) and 3 additional heterozygotes displayed borderline HCM; unaffected heterozygous carriers in the family were under the age of 30, suggesting this variant may cause late-onset and clinically silent disease (Andersen_2012). Therefore, this report does not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hypertrophic cardiomyopathy 8

Uncertain:1

Nov 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V79I variant (also known as c.235G>A), located in coding exon 3 of the MYL3 gene, results from a G to A substitution at nucleotide position 235. The valine at codon 79 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in an asymptomatic individual with hypertrophic cardiomyopathy (HCM), as well as in three family members with borderline HCM findings and in six unaffected carrier family members, including some who were children at the time of evaluation (Andersen PS et al. Biochem Res Int, 2012 Apr;2012:685108). This variant has also been reported as a secondary finding in exome cohorts with limited clinical details provided (Lawrence L et al. Genet Med, 2014 Oct;16:741-50; Olfson E et al. PLoS One, 2015 Sep;10:e0135193). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

CardioboostCm

Benign

0.014

BayesDel_addAF

Uncertain

0.048

T

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

25

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.89

D

LIST_S2

Uncertain

0.96

.;D

M_CAP

Benign

0.032

D

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Uncertain

-0.011

T

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.61

T

PROVEAN

Benign

-0.53

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.18

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.64

P;P

Vest4

0.69

MVP

0.85

MPC

0.34

ClinPred

0.24

T

GERP RS

4.4

Varity_R

0.12

gMVP

0.20

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.

rs150634297

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