rs28932774

Variant names:

• chr12-110919145-A-G
• rs104894370
• NM_000432.4:c.52T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000432.4(MYL2):​c.52T>C​(p.Phe18Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 8.90

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 Pathogenic. Variant got 14 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, 0.876
• PP5: Variant 12-110919145-A-G is Pathogenic according to our data. Variant chr12-110919145-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110919145-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.52T>C	p.Phe18Leu	missense_variant	Exon 2 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.52T>C	p.Phe18Leu	missense_variant	Exon 2 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.-6T>C		5_prime_UTR_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.52T>C	p.Phe18Leu	missense_variant	Exon 2 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.52T>C	p.Phe18Leu	missense_variant	Exon 2 of 6	3		ENSP00000447154.1
MYL2	ENST00000546404.1	c.52T>C	p.Phe18Leu	missense_variant	Exon 2 of 2	2		ENSP00000499645.1
MYL2	ENST00000663220.1	c.-6T>C		5_prime_UTR_variant	Exon 2 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461652 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000457 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Pathogenic:2 Other: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 phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 18 of the MYL2 protein (p.Phe18Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9535554). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14068). 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: 11102452, 12668451, 14594949, 25324513). This variant disrupts the Phe18 amino acid residue in MYL2. Other variant(s) that disrupt this residue have been observed in individuals with MYL2-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 26, 2012

Leiden Muscular Dystrophy (MYL2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

not provided Pathogenic:1

Mar 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect through decreased calcium sensitivity and altered phosphorylation (Szczesna et al., 2001; Roopnarine 2003; Szczesna-Cordary et al., 2004) ); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14594949, 25324513, 9535554, 12668451, 11102452) -

Hypertrophic cardiomyopathy 10;C5561937:Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy Pathogenic:1

Sep 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:1

Sep 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 11102452, 14594949, 25324513, 12668451). This variant has been reported in individuals with hypertrophic cardiomyopathy (PMID: 9535554, 12707239, 33495597). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in 8 affected individuals in one family (PMID: 9535554). This variant is predicted to be deleterious by in silico analysis. -

Cardiovascular phenotype Pathogenic:1

Nov 17, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F18L variant (also known as c.52T>C), located in coding exon 2 of the MYL2 gene, results from a T to C substitution at nucleotide position 52. The phenylalanine at codon 18 is replaced by leucine, an amino acid with highly similar properties. This variant has been described in patients with hypertrophic cardiomyopathy (HCM) (Flavigny J et al. J Mol Med. 1998;76(3-4):208-14; Richard P et al. Circulation. 2003;107(17):2227-32). This variant was observed to co-segregate with a clinical phenotype in eight relatives in a four-generation family with HCM; however, four additional relatives with this variant in the same family did not exhibit a clinical phenotype suggesting reduced penetrance or variable age of onset (Flavigny J et al. J Mol Med. 1998;76(3-4):208-14). Functional in vitro analyses indicate this variant disturbs Ca2+ sensitivity, thus reducing binding affinity and resulting in decreased cardiac contractile force and function (Szczesna D et al. J Biol Chem. 2001;276(10):7086-92; Roopnarine O. Biophys J. 2003;84(4):2440-9; Szczesna-Cordary D et al. J Biol Chem. 2004;279(5):3535-42; Farman GP et al. J Appl Physiol. 2014;117(12):1471-7). This variant was previously reported in the SNPDatabase as rs104894370. This variant was not reported in population-based cohorts in the following databases: 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, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		0.99	D;.
Vest4		0.89
MutPred		0.59		Gain of catalytic residue at N16 (P = 0.0192);Gain of catalytic residue at N16 (P = 0.0192);
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.82

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: rs104894370; hg19: chr12-111356949;