3-46860813-G-T

Variant names:

• chr3-46860813-G-T
• rs139794067
• NM_000258.3:c.170C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1 PM5 PP2 PP3_Moderate BS2

The NM_000258.3(MYL3):​c.170C>A​(p.Ala57Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. 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. A57G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:19 B:1
• Conservation: PhyloP100: 8.15
• Publications: 53 publications found

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]

MYL3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 8

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 16 pathogenic changes around while only 6 benign (73%) in NM_000258.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-46860813-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31780.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.75572 (below the threshold of 3.09). Trascript score misZ: 1.3243 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy 8.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• BS2: High AC in GnomAd4 at 20 AD,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000258.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL3	NM_000258.3	MANE Select	c.170C>A	p.Ala57Asp	missense	Exon 3 of 7	NP_000249.1
	MYL3	NM_001406937.1		c.170C>A	p.Ala57Asp	missense	Exon 3 of 6	NP_001393866.1
	MYL3	NM_001406938.1		c.170C>A	p.Ala57Asp	missense	Exon 5 of 9	NP_001393867.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL3	ENST00000292327.6	TSL:1 MANE Select	c.170C>A	p.Ala57Asp	missense	Exon 3 of 7	ENSP00000292327.4
	MYL3	ENST00000395869.5	TSL:1	c.170C>A	p.Ala57Asp	missense	Exon 3 of 6	ENSP00000379210.1
	MYL3	ENST00000713934.1		c.302C>A	p.Ala101Asp	missense	Exon 3 of 7	ENSP00000519231.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251470 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000116 AC: 170 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.000139 AC XY: 101 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000647 AC: 72 AN: 1112010

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74406

African (AFR) AF: 0.0000241 AC: 1 AN: 41522

American (AMR) AF: 0.000523 AC: 8 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:19 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Jun 27, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies using human induced pluripotent stem cell (iPSC) lines demonstrated that p.(A57D) expressed in the heterozygous and homozygous state did not produce an HCM phenotype (PMID: 29914921); This variant is associated with the following publications: (PMID: 29687901, 24111713, 27483260, 21239446, 27574918, 28971120, 28518168, 29914921, 30624779, 31006259, 23426552, 31019283, 33288880, 34636345, 34509299, 34137518, 33935716, 29710196, 26779504, 29343803, 35653365)

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 10, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3

Jun 29, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

MYL3 p.Ala57Asp (c.170C>A) (NM_000258.1) There is moderate case data with some segregation demonstrated, but the variant is also seen at relatively high frequency in population databases and has been seen in combination with a pathogenic variant and in a homozygous state in an unaffected individual. We consider this conflicting data and deem the variant to be a variant of uncertain significance. We do not feel that this variant is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in an individual with HCM. Testing was performed by Familion. The variant has been seen in at least 5 unrelated cases of HCM (not including this patient's family). There is conflicting case data. This variant has been reported in 1 individual with HCM by Fokstuen et al., 2011, and in 1 individual with HCM by Almaas et al., 2013. It has also been reported in a Korean family, segregating with disease in 5 individuals with HCM by Choi et al., 2010. Controls/Population data: The variant has not been seen in 400 Familion laboratory controls. The variant was reported online in 14 of 60,669 (0.023%) individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/25/16). Specifically, the variant was observed in following ethnicities European (Non-Finnish) 5/33,342; East Asian 3/4,323; Latino 1/5,787; South Asian 5/8,256. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

Hypertrophic cardiomyopathy 8 Pathogenic:1 Uncertain:3 Benign:1

Aug 11, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.89 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. A different missense change at the same codon (p.Ala57Gly) has been reported to be associated with MYL3 related disorder (PMID: 11174330). The same homozygous variantwas reported in a family with hypertrophic cardiomyopathy (PMID: 33288880). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYL3 NM_000258.2 exon 3 p.Ala57Asp (c.170C>A): This variant has been reported in the literature in several individuals with HCM (Fokstuen 2011 PMID:21239446, Almaas 2013 PMID:23426552, Berge 2014 PMID:24111713, Jaafar 2015 PMID:26779504, Rubatta 2016 PMID:27483260, Dejgaard 2017 PMID:28971120). This variant is present in 0.05% (17/30616) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-46902303-G-T) and is present in ClinVar (Variation ID:43121). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, autosomal recessive inheritance carrier status, and/or variable expressivity. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, another variant at the same amino acid (p.Ala57Gly) has been reported in association with disease. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 19, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The MYL3 Ala57Asp has been previously identified in HCM cases (Jaafar N, et al., 2016; Almaas VM, et al., 2013; Vazquez-Alvarez MC, et al., 2012; Fokstuen S et al., 2011; Calore C, et al., 2011; Choi JO, et al., 2010). The cases reported by Vazquez-Alvarez MC, et al. (2012) included a prenatal HCM case, however the patient was also diagnosed with Noonan syndrome. An iPSC-CM model showed that both heterozygous and homozygous cardiac cells did not produce an HCM phenotype (Ma N, et al., 2018). Interestingly a different change at this position (Ala57Gly) has been reported in multiple HCM cases, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, PolyPhen2 and MutationTaster predict this variant to have a deleterious effect. The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.0001588, which is higher then expected for HCM. We identified this variant in an HCM patient with a family history of HCM. A second variant (ACTC1 Ala323Val) was also identified in this patient. The ACTC1 variant was found to segregate to an affected fourth degree relative but MYL3 Ala57Asp did not segregate. The variant has been found to segregate with disease in two homozygous siblings reported by LMM (ClinVar: SCV000208872). In summary, based on the lack of phenotype in iPSC-CM, high allele frequency and non-segregation in affected family members, we classify MYL3 Ala57Asp (in the heterozygous form) as "likely benign".

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Hypertrophic cardiomyopathy Uncertain:5

Jun 23, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala57Asp variant in MYL3 has been reported in heterozygous state in at least 4 individuals with hypertrophic cardiomyopathy (Fokstuen 2011 PMID: 21239446, Almaas 2013 PMID: 23426552, Berge 2014 PMID: 24111713, Norrish 2019 PMID: 31006259, LMM data); two of these individuals were heterozygous for pathogenic variants in another gene. This variant has been identified in homozygous state in at least 2 individuals with cardiomyopathy (Osborn 2021 PMID: 33288880, LMM data). It has also been identified in 0.06% (17/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43121). 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 vitro functional studies provide conflicting evidence regarding the impact of this variant on protein function (Ma 2018 PMID: 29914921 , Osborn 2021 PMID: 33288880); however, these types of assays may not accurately represent biological function. Another variant involving this codon (p.Ala57Gly) has been identified in individuals with hypertrophic cardiomyopathy and is classified as uncertain significance by this laboratory. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, BP5.

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with aspartic acid at codon 57 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). A functional study with human-induced pluripotent stem cells has shown that this variant has no significant impact on MYL3 protein as determined by gene expression, sarcomere structure, cell size, contractility, action potentials and calcium handling (PMID: 29914921). However, another study with zebrafish knockdown model has shown that this variant is unable to rescue the compromised cardiac function as wild-type MYL3 does (PMID: 33288880). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 23426552, 24111713, 27483260, 27574918, 33288880, 34137518), including three unrelated homozygotes (PMID: 27574918, 33288880, 34137518). This variant has also been identified in 46/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with uncertain functional impact that has been observed in the control population as well as in affected individuals. 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.

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Genetics and Genomics Program, Sidra Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 57 of the MYL3 protein (p.Ala57Asp). This variant is present in population databases (rs139794067, gnomAD 0.06%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21239446, 23426552, 24111713, 27483260, 34137518, 36964972, 37431535, 37652022). ClinVar contains an entry for this variant (Variation ID: 43121). 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. Experimental studies have shown that this missense change does not substantially affect MYL3 function (PMID: 29914921). 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.

Cardiomyopathy Uncertain:3

Dec 03, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with aspartic acid at codon 57 of the MYL3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study with human-induced pluripotent stem cells has shown that this variant has no significant impact on MYL3 protein as determined by gene expression, sarcomere structure, cell size, contractility, action potentials and calcium handling (PMID: 29914921). However, another study with zebrafish knockdown model has shown that this variant is unable to rescue the compromised cardiac function as wild-type MYL3 does (PMID: 33288880). This variant has been reported in heterozygous multiple individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 23426552, 24111713, 27483260, 27574918, 33288880, 34137518, 37431535), as well as in five unrelated homozygous individuals (PMID: 27574918, 33288880, 34137518, 37431535). This variant has also been identified in 46/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with uncertain functional impact that has been observed in the control population as well as in affected individuals. 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.

MYL3-related disorder Uncertain:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYL3 c.170C>A variant is predicted to result in the amino acid substitution p.Ala57Asp. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Fokstuen et al. 2011. PubMed ID: 21239446; Berge et al. 2014. PubMed ID: 24111713; Almaas et al. 2013. PubMed ID: 23426552; Jaafar et al. 2015. PubMed ID: 26779504; Rubattu et al. 2016. PubMed ID: 27483260; Dejgaard et al. 2017. PubMed ID: 28971120; Table S10, Stava et al. 2022. PubMed ID: 35653365). This variant was also reported in the homozygous state to be associated with autosomal recessive HCM (Osborn et al. 2021. PubMed ID: 33288880). However, some individuals with this variant also carried additional variants in other HCM-related genes that are likely contributing to a HCM phenotype (Berge et al. 2014. PubMed ID: 24111713; Rubattu et al. 2016. PubMed ID: 27483260). Functional studies using human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) showed that both heterozygous and homozygous MYL3(170C>A)-iPSC-CMs did not reproduce a HCM phenotype (Ma et al. 2018. PubMed ID: 29914921). However, in another study, this variant failed to rescue the compromised cardiac function in a zebrafish knockdown model (Osborn et al. 2021. PubMed ID: 33288880). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Long QT syndrome Uncertain:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PP2, PP3, BS3

Primary familial hypertrophic cardiomyopathy Uncertain:1

Jul 07, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiovascular phenotype Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A57D variant (also known as c.170C>A), located in coding exon 3 of the MYL3 gene, results from a C to A substitution at nucleotide position 170. The alanine at codon 57 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant was reported in the heterozygous and homozygous states individual(s) with features consistent with hypertrophic cardiomyopathy (Fokstuen S et al. J Med Genet. 2011;48:572-6; Almaas VM et al. Europace. 2013;15:1319-27; Berge KE et al. Clin Genet. 2014;86:355-60; Rubattu S et al. Int J Mol Sci, 2016 Jul;17:1239; Oktay V et al. Anatol J Cardiol. 2023 Nov;27(11):628-638; Jaouadi H et al. Front Med (Lausanne). 2024 Oct;11:1480947; Ambry internal data). In some cases, there were unaffected heterozygous and homozygous family members of affected homozygotes (Jaafar N et al. Genet Test Mol Biomarkers. 2016;20:674-679; Osborn DPS et al. Genet Med, 2021 Apr;23:787-792). In addition, multiple probands with this variant have had additional pathogenic variants in other HCM-associated genes (Ambry internal data; Broendberg AK et al. Eur J Hum Genet, 2018 03;26:303-313). Furthermore, this variant did not demonstrate a deleterious impact in several functional assays performed in human induced pluripotent stem cells heterozygous or homozygous for this alteration, although zebrafish models showed only partial rescue; given that the molecular mechanisms underlying HCM are not fully understood, the physiological significance of these results is unclear (Ma N et al. Circulation. 2018;138:2666-2681; Osborn DPS et al. Genet Med, 2021 Apr;23:787-792). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.38
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		8.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.61		Gain of disorder (P = 0.0453)
MVP		0.91
MPC		1.4
ClinPred		0.84	D
GERP RS		4.4
Varity_R		0.95
gMVP		0.92
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139794067; hg19: chr3-46902303;