rs104894370

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-110919145-A-G
• chr12-110919145-A-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F18S) has been classified 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:7 O:1
• Conservation: PhyloP100: 8.90
• Publications: 16 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 22 pathogenic changes around while only 6 benign (79%) 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 chr12-110919144-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181425.
• 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, 0.876
• PP5: Variant 12-110919145-A-G is Pathogenic according to our data. Variant chr12-110919145-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000221 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 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

- -

Cardiomyopathy Pathogenic:1

Nov 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with leucine at codon 18 of the MYL2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies using in vitro assays of purified human MYL2 protein as well as rat myosin regulatory light chain have shown that this variant affects calcium sensitivity and reduces binding affinity, leading to impairment in cardiac contraction (PMID: 11102452, 12668451, 14594949). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 9535554, 12707239, 33495597). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 9535554). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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

Jan 24, 2025

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 was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least one family (Flavigny J et al. J Mol Med. 1998;76(3-4):208-14; Richard P et al. Circulation. 2003;107(17):2227-32; Ambry internal data). 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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;.
PhyloP100		8.9
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
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs104894370; hg19: chr12-111356949;