12-110914290-C-T

Variant names:

• chr12-110914290-C-T
• rs199474809
• NM_000432.4:c.170G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

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. 16/27 in silico tools predict a damaging outcome for this variant. 3/3 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:8 O:1
• Conservation: PhyloP100: 7.50
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000432.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.39564 (below the threshold of 3.09). Trascript score misZ: 1.1124 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 10, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, congenital fiber-type disproportion myopathy.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.170G>A	p.Gly57Glu	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.128G>A	p.Gly43Glu	missense_variant	Exon 3 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.113G>A	p.Gly38Glu	missense_variant, splice_region_variant	Exon 4 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.170G>A	p.Gly57Glu	missense_variant, splice_region_variant	Exon 4 of 7	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152056 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251442 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460564 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726698

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110824

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Other:1

-

Leiden Muscular Dystrophy (MYL2)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 12, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hypertrophic cardiomyopathy 10 Uncertain:2

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 37652022). 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. -

Aug 14, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly57Glu variant in the MYL2 gene has been previously reported in one individual with restrictive cardiomyopathy who was also found to be homozygous for a variant in MYL3 (p.Glu143Lys). This individual’s unaffected mother was heterozygous for the p.Gly57Glu variant as well as heterozygous for the p.Glu143Lys variant in MYL3 (Caleshu et al., 2011). This variant was also detected in two individuals with early-onset HCM (age 1 and 4 years) who both had a second MYL2 variant detected (p.Glu134Ala). In one of these individuals, the p.Glu134Ala variant was confirmed to be in trans (Alfares et al., 2015). This variant has been identified in 1/251,442 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of hypertrophic cardiomyopathy. The glycine at position 57 is evolutionarily conserved. Computational tools predict that the p.Gly57Glu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly57Glu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP3] -

not specified Uncertain:1

Jul 16, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 individual was heterozygous for this variant and homozygous for a likely pathogenic variant in the MYL3 gene. The individual's unaffected parent was a carrier of both variants. This variant has also been reported in two individuals affected with hypertrophic cardiomyopathy (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 Uncertain:1

Mar 05, 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 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. -

Cardiovascular phenotype Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G57E variant (also known as c.170G>A), located in coding exon 4 of the MYL2 gene, results from a G to A substitution at nucleotide position 170. This variant impacts the first base pair of coding exon 4. The glycine at codon 57 is replaced by glutamic acid, an amino acid with some similar properties. This alteration has been reported in a subject with restrictive cardiomyopathy who was also homozygous for a missense alteration in MYL3. The unaffected mother was heterozygous for both variants (Caleshu C et al. Am. J. Med. Genet. A, 2011 Sep;155A:2229-35). This variant has also been detected in a hypertrophic cardiomyopathy genetic testing cohort (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. Based on the available evidence, the clinical significance of this variant 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	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.91	D
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	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.95
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs199474809; hg19: chr12-111352094;