12-110911095-G-T

Position:

• chr12-110911095-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000432.4(MYL2):​c.483C>A​(p.His161Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H161R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:2
• Conservation: PhyloP100: -1.66

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 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-110911096-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.483C>A	p.His161Gln	missense_variant	7/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.441C>A	p.His147Gln	missense_variant	6/6		NP_001393674.1
MYL2	NM_001406916.1	c.426C>A	p.His142Gln	missense_variant	7/7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.483C>A	p.His161Gln	missense_variant	7/7	1	NM_000432.4	ENSP00000228841	P1
MYL2	ENST00000548438.1	c.441C>A	p.His147Gln	missense_variant	6/6	3		ENSP00000447154
MYL2	ENST00000663220.1	c.426C>A	p.His142Gln	missense_variant	7/7			ENSP00000499568

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypertrophic cardiomyopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 264266). 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 histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the MYL2 protein (p.His161Gln). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2015

The p.H161Q variant (also known as c.483C>A), located in coding exon 7 of the MYL2 gene, results from a C to A substitution at nucleotide position 483. The histidine at codon 161 is replaced by glutamine, an amino acid with highly similar properties. This variant has not been previously reported in association with hypertrophic cardiomyopathy (HCM). Another alteration in the same codon, p.H161R (c.482A>G), has been reported in association with HCM (Helms AS et al. Circ Cardiovasc Genet. 2014; 7(4):434-43). The p.H161Q variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.85	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.056	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.42		Loss of glycosylation at K165 (P = 0.1565);.;
MVP		0.87
MPC		1.2
ClinPred		0.99	D
GERP RS		-0.80
Varity_R		0.93
gMVP		0.63

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: rs886039108; hg19: chr12-111348899;