12-110911090-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000432.4(MYL2):c.488A>C(p.Glu163Ala) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E163G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.63

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr12-110911090-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181421.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821
• PP5: Variant 12-110911090-T-G is Pathogenic according to our data. Variant chr12-110911090-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43480.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.488A>C	p.Glu163Ala	missense_variant	7/7	ENST00000228841.15
MYL2	NM_001406745.1	c.446A>C	p.Glu149Ala	missense_variant	6/6
MYL2	NM_001406916.1	c.431A>C	p.Glu144Ala	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.488A>C	p.Glu163Ala	missense_variant	7/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.446A>C	p.Glu149Ala	missense_variant	6/6	3
MYL2	ENST00000663220.1	c.431A>C	p.Glu144Ala	missense_variant	7/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 163 of the MYL2 protein (p.Glu163Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961). ClinVar contains an entry for this variant (Variation ID: 43480). An algorithm developed specifically for the MYL2 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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. -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2013

The Glu163Ala variant in MYL2 has not been reported in the literature, but has b een identified by our laboratory in 2 individuals with HCM (LMM unpublished data ). This variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS), which increases the likelihood that the variant is patho genic. However, we cannot exclude that it may be common in other populations. Gl utamic acid (Glu) at position 163 is highly conserved in mammals and across evol utionarily distant species and the change to alanine (Ala) was predicted to be p athogenic using a computational tool clinically validated by our laboratory. Thi s tool's pathogenic prediction is estimated to be correct 94% of the time (Jorda n 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 01, 2019

Variant summary: MYL2 c.488A>C (p.Glu163Ala) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249808 control chromosomes. c.488A>C has been reported in the literature in at-least two individuals affected with Hypertrophic Cardiomyopathy (Bos_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Another submitter in ClinVar prior to 2014 states that the variant was observed in two individuals with HCM at their laboratory, however contradicts this by reporting no occurrences in individuals with HCM in a database produced by their institution (Atlas of Cardiac Genetic Variation). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
CardioboostCm	Uncertain	0.90
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.30	T;T
Polyphen		0.99	D;.
Vest4		0.73
MutPred		0.30		Gain of catalytic residue at E163 (P = 2e-04);.;
MVP		0.88
MPC		1.1
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.68

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: rs397516407; hg19: chr12-111348894;