rs397516408

chr12-110919117-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 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

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 6 ACMG points.

• PM1: In a domain EF-hand 1 (size 35) in uniprot entity MLRV_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 43481.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr12-110919117-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.80A>G	p.Gln27Arg	missense_variant	2/7	ENST00000228841.15
MYL2	NM_001406745.1	c.80A>G	p.Gln27Arg	missense_variant	2/6
MYL2	NM_001406916.1	c.23A>G	p.Gln8Arg	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.80A>G	p.Gln27Arg	missense_variant	2/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.80A>G	p.Gln27Arg	missense_variant	2/6	3
MYL2	ENST00000663220.1	c.23A>G	p.Gln8Arg	missense_variant	2/7
MYL2	ENST00000546404.1	c.80A>G	p.Gln27Arg	missense_variant	2/2	2

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

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 10, 2012

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. -

Hypertrophic cardiomyopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 25, 2022

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;.
MutationTaster	Benign	1.0	D;D
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

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: rs397516408; hg19: chr12-111356921;