NM_000432.4:c.173G>A

Variant names:

• chr12-110914287-C-T
• rs104894369
• NM_000432.4:c.173G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000432.4(MYL2):​c.173G>A​(p.Arg58Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,934 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000549157: Experimental studies have shown that this missense change affects MYL2 function (PMID:14594949, 19150977, 20855589, 21723297, 23727233, 26116789)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58L) has been classified as Likely pathogenic. The gene MYL2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.50
• Publications: 67 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: Labcorp Genetics (formerly Invitae), G2P
• 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

Specifications for MYL2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000549157: Experimental studies have shown that this missense change affects MYL2 function (PMID: 14594949, 19150977, 20855589, 21723297, 23727233, 26116789).; SCV002318578: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product." PMID: 14594949, 19150977; SCV006059814: Functional studies conducted in non-human animal models demonstrated that this variant impacts protein function (PMID: 16837010; 19150977).; SCV000208858: Published functional studies demonstrate a damaging effect as the p.(R58Q) residue is in a calcium binding site within the human cardiac regulatory light chain; p.(R58Q) eliminates normal calcium binding and increases the calcium sensitivity of myofibrillar ATPase (Szczesna et al., 2001; Szczesna-Cordary et al., 2004; Greenberg et al., 2009; Wang et al., 2013); SCV000280383: Functional studies of this variant indicate that it is in a calcium binding site within the human cardiac regulatory light chain and Arg58Gln eliminates normal calcium binding and increases the calcium sensitively of myofibrillar ATPase, which is proposed to affect regulation of cardiac muscle contraction (Szczesna-Cordary et al., 2004).; SCV005879041: Multiple functional analyses show affected function of MYL2: abolished calcium binding when nonphosphorylated, increased calcium sensitivity of myofibrillar ATPase activity, altered contraction kinetics of cardiac muscle, and altered cross-bridge kinetics (Greenberg 2009, Greenberg 2010, Mettikolla 2011, Szczesna 2001, Szczesna-Cordary 2004, Wang 2013).; SCV000740066: In addition, a number of in vitro studies suggested that this variant would abolish calcium binding and alter the contraction kinetics of cardiac muscle (Szczesna D et al. J. Biol. Chem., 2001 Mar;276:7086-92; Greenberg MJ et al. J. Mol. Cell. Cardiol., 2009 Jan;46:108-15; Greenberg MJ et al. Proc. Natl. Acad. Sci. U.S.A., 2010 Oct;107:17403-8; Wang Y et al. J. Mol. Biol., 2006 Aug;361:286-99; Mettikolla P et al. J. Theor. Biol., 2011 Sep;284:71-81; Wang L et al. J. Mol. Cell. Cardiol., 2013 Sep;62:153-63).; SCV000060038: "In vitro functional studies provide some evidence that the p.Arg58Gln variant may impact protein function." (Szczesna 2001,Szczesna-Cordary 2004, Greenberg 2009, Greenberg 2010, Mettikolla 2011, Wang 2013)
• PM1: In a domain EF-hand 1 (size 35) in uniprot entity MLRV_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr12-110914287-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 532778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, hypertrophic cardiomyopathy 10, congenital fiber-type disproportion myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 12-110914287-C-T is Pathogenic according to our data. Variant chr12-110914287-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000432.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	NM_000432.4	MANE Select	c.173G>A	p.Arg58Gln	missense	Exon 4 of 7	NP_000423.2	P10916
	MYL2	NM_001406745.1		c.131G>A	p.Arg44Gln	missense	Exon 3 of 6	NP_001393674.1	G3V1V8
	MYL2	NM_001406916.1		c.116G>A	p.Arg39Gln	missense	Exon 4 of 7	NP_001393845.1	A0A590UJU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	ENST00000228841.15	TSL:1 MANE Select	c.173G>A	p.Arg58Gln	missense	Exon 4 of 7	ENSP00000228841.8	P10916
	MYL2	ENST00000713800.1		c.173G>A	p.Arg58Gln	missense	Exon 5 of 8	ENSP00000519106.1	P10916
	MYL2	ENST00000713803.1		c.173G>A	p.Arg58Gln	missense	Exon 5 of 8	ENSP00000519109.1	P10916

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460934 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726836

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111138

Other (OTH) AF: 0.0000166 AC: 1 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Hypertrophic cardiomyopathy 10 (6)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.65	N
PhyloP100		7.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.57
Sift	Benign	0.14	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.89
MVP		0.88
MPC		1.1
ClinPred		0.80	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.85
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894369; hg19: chr12-111352091;