12-110911081-T-A

Variant names:

• chr12-110911081-T-A
• rs199474815
• NM_000432.4:c.497A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000432.4(MYL2):​c.497A>T​(p.Asp166Val) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.27

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 8 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, 0.875
• PP5: Variant 12-110911081-T-A is Pathogenic according to our data. Variant chr12-110911081-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 31769.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-110911081-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.497A>T	p.Asp166Val	missense_variant	Exon 7 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.455A>T	p.Asp152Val	missense_variant	Exon 6 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.440A>T	p.Asp147Val	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.497A>T	p.Asp166Val	missense_variant	Exon 7 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.455A>T	p.Asp152Val	missense_variant	Exon 6 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.440A>T	p.Asp147Val	missense_variant	Exon 7 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 166 of the MYL2 protein (p.Asp166Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31769). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYL2 function (PMID: 18987303, 23727233, 24374283). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Asp166 amino acid residue in MYL2. Other variant(s) that disrupt this residue have been observed in individuals with MYL2-related conditions (PMID: 24793961; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Other:1

Mar 26, 2012

Leiden Muscular Dystrophy (MYL2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
CardioboostCm	Uncertain	0.68
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;.
Vest4		0.81
MutPred		0.50		Gain of catalytic residue at E163 (P = 0.094);.;
MVP		0.93
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
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

Other links and lift over

dbSNP: rs199474815; hg19: chr12-111348885;