rs397516399

Variant names:

• chr12-110914200-C-G
• rs397516399
• NM_000432.4:c.260G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-110914200-C-G
• chr12-110914200-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_000432.4(MYL2):​c.260G>C​(p.Gly87Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G87E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.85
• Publications: 3 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: Likely_pathogenic. The variant received 9 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-110914200-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571147.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• 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: MetaRNN computational evidence supports a deleterious effect, 0.84
• PP5: Variant 12-110914200-C-G is Pathogenic according to our data. Variant chr12-110914200-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43461.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.218G>C	p.Gly73Ala	missense_variant	Exon 3 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.203G>C	p.Gly68Ala	missense_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.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 7	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Feb 16, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly87Ala variant in MYL2 has been identified by our laboratory in 2 indivi duals with HCM and segregated with disease in 4 affected relatives. It has not b een identified in large population studies. This variant was predicted to be pat hogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish i ts clinical significance, the p.Gly87Ala variant is likely pathogenic. -

not provided Uncertain:1

Oct 11, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with HCM, though patient-specific clinical and family data were not provided (Lopes et al., 2015; Walsh et al., 2017; Norrish et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25351510, 27532257, 31006259) -

Cardiovascular phenotype Uncertain:1

Mar 25, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G87A variant (also known as c.260G>C), located in coding exon 4 of the MYL2 gene, results from a G to C substitution at nucleotide position 260. The glycine at codon 87 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in multiple hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Norrish G et al. Circulation, 2019 Jul;140:184-192). Furthermore, two different variants impacting the same amino acid, p.G87E and p.G87W, have also been reported in hypertrophic cardiomyopathy (HCM) cohorts with limited clinical information provided (Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Wang J et al. Eur. J. Heart Fail., 2014 Sep;16:950-7). 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	Pathogenic	0.80
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Benign	0.60	N;.
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.091	T;T
Sift4G	Benign	0.25	T;T
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.48		Loss of ubiquitination at K91 (P = 0.1066);.;
MVP		0.91
MPC		1.2
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.78
gMVP		0.86
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516399; hg19: chr12-111352004;