rs397516408

Variant names:

• chr12-110919117-T-C
• rs397516408
• NM_000432.4:c.80A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_000432.4(MYL2):​c.80A>G​(p.Gln27Arg) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q27H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.64
• Publications: 1 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 7 ACMG points.

• PM1: In a domain EF-hand 1 (size 35) in uniprot entity MLRV_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.824
• PP5: Variant 12-110919117-T-C is Pathogenic according to our data. Variant chr12-110919117-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43481.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.80A>G	p.Gln27Arg	missense_variant	Exon 2 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.80A>G	p.Gln27Arg	missense_variant	Exon 2 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.23A>G	p.Gln8Arg	missense_variant	Exon 2 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.80A>G	p.Gln27Arg	missense_variant	Exon 2 of 7	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Dec 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln27Arg variant in MYL2 has not been reported in the literature, but has be en identified in one individual with HCM previously tested by our laboratory and segregated with disease in one affected relative in this family (LMM unpublishe d data). This variant has also not been identified in large and broad European A merican and African American populations by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS); this low frequency is consistent with a disea se causing role but insufficient to establish this with confidence. Glutamine (G ln) at position 27 is highly conserved in mammals and across evolutionarily dist ant species and the change to Arginine (Arg) was predicted to be pathogenic usin g a computational tool clinically validated by our laboratory. This tool's patho genic prediction is estimated to be correct 94% of the time (Jordan 2011). In su mmary, this variant is likely to be pathogenic, though additional studies are re quired to fully establish its clinical significance. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 10 Uncertain:1

Apr 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 27 of the MYL2 protein (p.Gln27Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43481). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.062	T;D
Polyphen		0.97	D;.
Vest4		0.80
MutPred		0.40		Gain of catalytic residue at I26 (P = 0.0084);Gain of catalytic residue at I26 (P = 0.0084);
MVP		0.91
MPC		1.1
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.84
gMVP		0.84
Mutation Taster		=64/36	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: rs397516408; hg19: chr12-111356921;