rs375667565

chr12-110913124-G-Achr12-110913124-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000432.4(MYL2):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T125K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 9.55

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_benign. Variant got -2 ACMG points.

• PM1: In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 53 pathogenic changes around while only 9 benign (85%) in NM_000432.4
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.374C>T	p.Thr125Met	missense_variant	6/7	ENST00000228841.15
MYL2	NM_001406745.1	c.332C>T	p.Thr111Met	missense_variant	5/6
MYL2	NM_001406916.1	c.317C>T	p.Thr106Met	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.374C>T	p.Thr125Met	missense_variant	6/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.332C>T	p.Thr111Met	missense_variant	5/6	3
MYL2	ENST00000663220.1	c.317C>T	p.Thr106Met	missense_variant	6/7
MYL2	ENST00000549029.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251492 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID 43473; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33297573) -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 03, 2021	This missense variant replaces threonine with methionine at codon 125 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33297573). This variant has also been identified in 30/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 06, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 27, 2011

Variant classified as Uncertain Significance - Favor Benign. The Thr125Met varia nt in MYL2 has been identified in 1/8600 European American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). and in 1 indiv idual with HCM (this individual's relative, who carries a pathogenic MYBPC3 vari ant). Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an i mpact to the protein. Additional studies are needed to fully assess its clinical significance. -

Hypertrophic cardiomyopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the MYL2 protein (p.Thr125Met). This variant is present in population databases (rs375667565, gnomAD 0.1%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33297573, 34598319, 35626289). ClinVar contains an entry for this variant (Variation ID: 43473). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 15, 2023

This missense variant replaces threonine with methionine at codon 125 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33297573). This variant has also been identified in 30/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2018

The c.374C>T (p.T125M) alteration is located in exon 6 (coding exon 6) of the MYL2 gene. This alteration results from a C to T substitution at nucleotide position 374, causing the threonine (T) at amino acid position 125 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;.
Vest4		0.69
MVP		0.98
MPC		1.2
ClinPred		0.67	D
GERP RS		5.1
Varity_R		0.36
gMVP		0.65

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: rs375667565; hg19: chr12-111350928;