rs199474809

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_000432.4(MYL2):c.170G>A(p.Gly57Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. 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. G57R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYL2
NM_000432.4 missense, splice_region

Scores

Splicing: ADA: 0.9992

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:1

Conservation

PhyloP100: 7.50

Variant links:

Genes affected

MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]

MYL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000432.4

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYL2	NM_000432.4 linkuse as main transcript	c.170G>A	p.Gly57Glu	missense_variant, splice_region_variant	4/7	ENST00000228841.15
MYL2	NM_001406745.1 linkuse as main transcript	c.128G>A	p.Gly43Glu	missense_variant	3/6
MYL2	NM_001406916.1 linkuse as main transcript	c.113G>A	p.Gly38Glu	missense_variant, splice_region_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MYL2	ENST00000228841.15 linkuse as main transcript	c.170G>A	p.Gly57Glu	missense_variant, splice_region_variant	4/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1 linkuse as main transcript	c.128G>A	p.Gly43Glu	missense_variant	3/6	3
MYL2	ENST00000663220.1 linkuse as main transcript	c.113G>A	p.Gly38Glu	missense_variant, splice_region_variant	4/7
MYL2	ENST00000549029.1 linkuse as main transcript	n.1G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

251442

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460564

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726698

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 12, 2020	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (MYL2)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2017	The G57E variant has been reported in one individual with restrictive cardiomyopathy (Caleshu C et al., 2011). This patient was a 22-year-old female who was homozygous for a E143L variant in the MYL3 gene, and heterozygous for the G57E variant in the MYL2 gene. Her unaffected mother was heterozygous for both changes. G57E results in a non-conservative amino acid substitution of a non-polar Glycine residue with a negatively charged Glutamic acid residue at a position that is conserved through evolution. Missense variants in nearby residues (N47K, R58Q, E65K) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the G57E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 16, 2018

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly57Glu variant in MYL2 has been reported in one individual with clinical features of RC M, who also carried the homozygous p.Glu134Lys missense variant in MYL3 and whos e unaffected mother was heterozygous for both variants (Caleshu 2011). The p.Gly 57Glu variant in MYL2 has also been identified in 2 infants with HCM, both of wh om also carried another variant of uncertain significance (p.Glu134Ala) in MYL2 (LMM data). In one of these probands, the p.Gly57Glu variant was found to be pat ernally inherited and the proband's father had LVH. The p.Gly57Glu variant has b een identified in 1/33580 of Latino chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools an d conservation analysis suggest that the p.Gly57Glu variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In addition, this variant is located in the first base of the exon, which is pa rt of the 3? splice region; however, computational splicing prediction tools do not suggest an impact to splicing. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Gly57Glu variant is uncer tain. ACMG/AMP Criteria applied: PM2, PP3, PS4_Supporting. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 28, 2023

This missense variant replaces glycine with glutamic acid at codon 57 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with restrictive cardiomyopathy (PMID: 21823217). This patient was heterozygous for this variant and homozygous for a p.Glu143Leu variant in the MYL3 gene. The patient's unaffected mother was double heterozygous for both variants. This variant has also been reported in two individuals affected with hypertrophic cardiomyopathy, both of whom also carried the MYL3 p.Glu134Ala variant (PMID: 25611685, 27532257). This variant has been identified in 1/251442 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. -

Hypertrophic cardiomyopathy 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 57 of the MYL2 protein (p.Gly57Glu). This variant is present in population databases (rs199474809, gnomAD 0.003%). This missense change has been observed in individual(s) with restrictive cardiomyopathy and hypertrophic cardiomyopathy (PMID: 21823217, 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 43458). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2020

The p.G57E variant (also known as c.170G>A) is located in coding exon 4 of the MYL2 gene, results from a G to A substitution at nucleotide position 170. This change occurs in the first base pair of coding exon 4. This alteration changes the glycine at codon 57 to glutamic acid, an amino acid with some similar properties. This alteration has been reported in a subject with restrictive cardiomyopathy who also was homozygous for a missense alteration in MYL3. The subject's unaffected mother was heterozygous for this alteration as well as for the missense alteration in MYL3 (Caleshu C et al. Am. J. Med. Genet. A, 2011 Sep;155A:2229-35). This variant was also detected in an hypertrophic cardiomyopathy testing cohort; however, clinical details were not provided (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Pathogenic

1.0

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.44

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.93

MVP

0.99

MPC

1.4

ClinPred

1.0

GERP RS

4.9

Varity_R

0.89

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.52

Position offset: 34

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