12-110911090-T-C

Variant names:

• chr12-110911090-T-C
• rs397516407
• NM_000432.4:c.488A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000432.4(MYL2):​c.488A>G​(p.Glu163Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.63

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 12-110911090-T-C is Pathogenic according to our data. Variant chr12-110911090-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181421.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.488A>G	p.Glu163Gly	missense_variant	Exon 7 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.446A>G	p.Glu149Gly	missense_variant	Exon 6 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.431A>G	p.Glu144Gly	missense_variant	Exon 7 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.488A>G	p.Glu163Gly	missense_variant	Exon 7 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.446A>G	p.Glu149Gly	missense_variant	Exon 6 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.431A>G	p.Glu144Gly	missense_variant	Exon 7 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Aug 27, 2013

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted p.Glu163Gly (GAA>GGA): c.488 A>G in exon 7 of the MYL2 gene (NM_000432.3). The Glu163Gly variant in the MYL2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu163Gly results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a non-polar Glycine at a position that is conserved across species. In silico analysis predicts Glu163Gly is damaging to the protein structure/function. Mutations in nearby residues (Gly162Arg, Asp166Val) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the Glu163Gly 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. In summary, while Glu163Gly is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s). -

not specified Uncertain:1

Apr 09, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu163Gly (c.488A>G). To the best of our knowledge, this p.Glu163Gly variant is novel and has not been reported in association with disease or in publicly available general population datasets. This variant results in a non-conservative amino acid substitution, where a negatively charged glutamic acid is exchanged for a nonpolar glycine. The glutamic acid at this position is completely conserved in available primates and other vertebrates, as are neighboring amino acids. In silico models consistently predict this variant to be damaging (including PolyPhen and Mutation Taster). Variants in nearby residues and at this exact residue have been reported in association with HCM in the literature and per report by an outside clinical laboratory, including Gly161Arg, Gly162Arg, Asp166Ala and Gly162Glu. A variant at the same residue, p.Glu163Ala, currently considered likely pathogenic by the LMM is currently in ClinVar (SCV000060064). This variant has been seen in two unrelated families with HCM by the LMM. No details regarding segregation with disease or whether alternative variants were detected in those families were reported. LMM reports that they have not seen this patient’s p.Glu163Gly variant to date. Pathogenic variants in the MYL2 gene, which encodes myosin regulatoray light chain 2, have been reported in association with HCM in the literature; however it is not known what percentage of individuals with familial HCM have a pathogenic variant in this gene. In total, this variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 163 listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 individuals of European and African American descent (as of January 8, 2015). Note, this does not match the patient’s ancestry (Mexico). There is also no variation at this codon listed in the Broad ExAC database, which includes variant calls on 65,000 individuals of varying ancestries (including 5,795 individuals with reported Latino ancestry). There is also no variation at this codon in dbSNP or 1000Genomes (as of January 8, 2015). -

Hypertrophic cardiomyopathy 10 Uncertain:1

Apr 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Glu163 amino acid residue in MYL2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24793961; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 181421). This variant has not been reported in the literature in individuals affected with MYL2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 163 of the MYL2 protein (p.Glu163Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
CardioboostCm	Uncertain	0.87
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.034	D;T
Polyphen		1.0	D;.
Vest4		0.64
MutPred		0.23		Gain of catalytic residue at H161 (P = 0.0211);.;
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.71

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

Other links and lift over

dbSNP: rs397516407; hg19: chr12-111348894;