rs193922391

chr3-46858413-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000258.3(MYL3):c.530A>G(p.Glu177Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,896 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:17
• Conservation: PhyloP100: 7.83

Genes affected

MYL3 (HGNC:7584): (myosin light chain 3) MYL3 encodes myosin light chain 3, an alkali light chain also referred to in the literature as both the ventricular isoform and the slow skeletal muscle isoform. Mutations in MYL3 have been identified as a cause of mid-left ventricular chamber type hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 36 pathogenic changes around while only 6 benign (86%) in NM_000258.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL3	NM_000258.3	c.530A>G	p.Glu177Gly	missense_variant	5/7	ENST00000292327.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL3	ENST00000292327.6	c.530A>G	p.Glu177Gly	missense_variant	5/7	1	NM_000258.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251212 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135778

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	Reported in association with hypertrophic cardiomyopathy (Bick et al., 2012; Jay et al., 2013); 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: 25637381, 22958901, 23594557, 25351510, 30706179, 31618753) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces glutamic acid with glycine at codon 177 of the MYL3 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 an infant affected with hypertrophic cardiomyopathy as well as his asymptomatic father (PMID: 23594557). This variant has also been reported in another four individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 30847666; ClinVar SCV000740165.3 and SCV000208890.11), in one individual with abnormality of the cardiovascular system (PMID: 26633542), in one individual affected with cardiomyopathy and progressive muscle weakness (PMID: 31618753), and in an individual with left ventricular wall thickness, left ventricular diastolic diameter and left atrial diameter within the normal range (PMID: 22958901). This variant has been identified in 16/282568 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Glu177Gly variant in MYL3 has been reported in at least 5 individuals with HCM (Jay 2013 PMID: 23594557, Lopes 2015 PMID: 25351510; Burstein 2021 PMID: 32746448, Ambry and GeneDx personal communication; ClinVar Variation ID 36648), but was also identified in 0.3% (1/316) of Middle Eastern and 0.02% (1/3470) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database, v. 3 (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922391). This variant has also been reported in ClinVar (Variation ID 36648). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu177Gly variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PP3, BS1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 177 of the MYL3 protein (p.Glu177Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23594557, 31618753, 32746448; Invitae). ClinVar contains an entry for this variant (Variation ID: 36648). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2018	Variant summary: MYL3 c.530A>G (p.Glu177Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 121730 control chromosomes. The observed variant frequency is approximately 1.97 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYL3 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05). However, only 6 occurrences were found in controls, which is too low to make a conclusion. c.530A>G has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 08, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu177Gly (c.530A>G). We consider it a variant of unknown significant, primarily based on a lack of strength in the available case data and a lack of controls matching our patient’s ancestry (and ancestry of one of the cases). One case was reported by Jay et al (2013): an Iraqi-American baby HCM with only this variant found on an 18 gene panel at GeneDx. The proband's father also carried the variant and reportedly had a normal echo (though not reviwed by the authors). MYL3 is one of the rarer HCM genes and it has not been studied as extensively as the more common ones. In a meta-analysis that included sequencing of MYL3 in 883 patients with HCM from several different centers, only one individual had an MYL3 variant thought to be disease causing (van Driest et al 2005). MYL3 was first linked to HCM in 1996 when a group from the NIH identified p.Met149Val in 1 of 383 unrelated HCM patients in their cohort (Poetter et al 1996). The variant segregated with disease in 12 affected family members with a LOD score of 6.2. Of note, p.Met149Val was not observed in the ~5400 individuals in the current version of the NHLBI ESP data set (June 25th, 2012). This is a non-conservative amino acid change with a polar Glutamine replaced with a non-polar Glycine. Conservation analysis indicates that Glutamine is highly conserved at this position in the MYL3 gene. In silico analysis predicts the amino acid change to be probably damaging to the protein (Ramensky V et al 2002). In addition, GeneDx noted that they found a nearby variant (p.Met173Val) in HGMD that was reported in association with HCM. In total, the variant has been seen in 2/8666 publicly available general population samples and private laboratory controls. Note that none of these samples match the patient’s ancestry. GeneDx reports that p.Glu177Gly was not identified in 200 presumably healthy control individuals of either Caucasian or African American ancestry. The variant has not been reported in dbSNP or 1000Genomes (as of June 2012). The variant is reported in 1/4,300 Caucasian individuals and 0/2,203 African American individuals in the NHLBI ESP dataset (as of June 25th, 2012). The phenotype of that particular individual is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The Seidman group observed the variant in 1 of 1963 unrelated individuals from the Jackson Heart Study (Bick et al 2012). That individual had a left ventricular wall thickness of 1.1 cm and two physiological risk factors (could include hyperlipidemia, hypertension, obesity, or diabetes). -

Hypertrophic cardiomyopathy 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense variant c.530A>G(p.Glu177Gly) in MYL3 gene has been reported in an infant affected with hypertrophic cardiomyopathy (Jay et. al., 2013). His father who also carried the variant was asymptomatic. This variant has also been reported in an individual with left ventricular wall thickness, left ventricular diastolic diameter and left atrial diameter within the normal range (Bick et. al., 2012). The p.Glu177Gly variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.005% in gnomAD exomes database. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Glu177Gly in MYL3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 177 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 22, 2023	This missense variant replaces glutamic acid with glycine at codon 177 of the MYL3 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). This variant does not affect the rate of myosin interaction with actin but increasing calcium sensitivity (PMID: 36509720). This variant has been reported in an infant affected with hypertrophic cardiomyopathy as well as his asymptomatic father (PMID: 23594557). This variant has also been reported in nine additional individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 30847666, 31618753, 32746448, 37431535), and in one individual with abnormality of the cardiovascular system (PMID: 26633542). This variant has also been observed in several unaffected individuals (PMID: 22958901, 37431535). This variant has been identified in 16/282568 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 18, 2022	- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2022

The c.530A>G (p.E177G) alteration is located in exon 5 (coding exon 5) of the MYL3 gene. This alteration results from a A to G substitution at nucleotide position 530, causing the glutamic acid (E) at amino acid position 177 to be replaced by a glycine (G). 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	Pathogenic	0.95
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.98	D;D
Vest4		0.93
MVP		0.90
MPC		1.2
ClinPred		0.57	D
GERP RS		3.8
Varity_R		0.66
gMVP		0.78

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: rs193922391; hg19: chr3-46899903;