rs104894370

chr12-110919145-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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:5 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 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain 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 id is 181425.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.
• 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/exons	MANE	UniProt
MYL2	NM_000432.4	c.52T>C	p.Phe18Leu	missense_variant	2/7	ENST00000228841.15
MYL2	NM_001406745.1	c.52T>C	p.Phe18Leu	missense_variant	2/6
MYL2	NM_001406916.1	c.-6T>C		5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.52T>C	p.Phe18Leu	missense_variant	2/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.52T>C	p.Phe18Leu	missense_variant	2/6	3
MYL2	ENST00000546404.1	c.52T>C	p.Phe18Leu	missense_variant	2/2	2
MYL2	ENST00000663220.1	c.-6T>C		5_prime_UTR_variant	2/7

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MYL2 function (PMID: 11102452, 12668451, 14594949, 25324513). 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: 14068). 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. This variant is not present in population databases (gnomAD no frequency). 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL2)	Mar 26, 2012	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2022

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 03, 2021

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2015

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;.
MutationTaster	Benign	1.0	A;A
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;