rs397516399

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The ENST00000228841.15(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 Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MYL2
ENST00000228841.15 missense

Scores

7
9
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 5.85
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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, 8 uncertain in ENST00000228841.15
PM2
Very rare variant in population databases, with high coverage;
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 submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr12-110914200-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYL2NM_000432.4 linkuse as main transcriptc.260G>C p.Gly87Ala missense_variant 4/7 ENST00000228841.15 NP_000423.2
MYL2NM_001406745.1 linkuse as main transcriptc.218G>C p.Gly73Ala missense_variant 3/6 NP_001393674.1
MYL2NM_001406916.1 linkuse as main transcriptc.203G>C p.Gly68Ala missense_variant 4/7 NP_001393845.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYL2ENST00000228841.15 linkuse as main transcriptc.260G>C p.Gly87Ala missense_variant 4/71 NM_000432.4 ENSP00000228841 P1
MYL2ENST00000548438.1 linkuse as main transcriptc.218G>C p.Gly73Ala missense_variant 3/63 ENSP00000447154
MYL2ENST00000663220.1 linkuse as main transcriptc.203G>C p.Gly68Ala missense_variant 4/7 ENSP00000499568
MYL2ENST00000549029.1 linkuse as main transcriptn.91G>C non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 16, 2017The 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
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 11, 2019Reported 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 25, 2020The 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;.
MutationTaster
Benign
1.0
D;D
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

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.

Other links and lift over

dbSNP: rs397516399; hg19: chr12-111352004; API