rs878854502

chr14-23384530-CC-TT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP6

The NM_002471.4(MYH6):c.5476_5477delinsAA(p.Gly1826Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1826R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.361

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH6
• BP6: Variant 14-23384530-CC-TT is Benign according to our data. Variant chr14-23384530-CC-TT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239179.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.5476_5477delinsAA	p.Gly1826Asn	missense_variant	36/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.5476_5477delinsAA	p.Gly1826Asn	missense_variant	36/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 14 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces glycine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1826 of the MYH6 protein (p.Gly1826Asn). 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 individual(s) with MYH6-related conditions (PMID: 15998695, 27600940). ClinVar contains an entry for this variant (Variation ID: 239179). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - This deletion insertion variant is predicted to result in a missense amino acid change from a glycine to an asparagine (exon 36). (N) 0251 - Variant is heterozygous. (N) 0303 - Variant is present in gnomAD (v3) >=0.01 enriched in the Amish sub-population for a dominant condition (54 heterozygotes, 0 homozygotes). (B) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif (myosin tail domain; NCBI, PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. Alternative changes at the same residue, to aspartic acid and serine, have previously been reported as pathogenic, VUS and likely benign in patients with cardiomyopathies and atrial septal defect; however it is unclear whether these previous reports represent single discrete variants, or a combination of two nucleotide changes in cis, resulting in the same change to asparagine (ClinVar, LOVD, PMID: 23396983, PMID: 29332214). (N) 0808 - Previous reports of pathogenicity are conflicting. The variant has previously been reported as pathogenic, a VUS, likely benign and as a rare SNP in cardiomyopathy patients (ClinVar, HGMD, LOVD, PMID: 15998695, PMID: 27600940). (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Conduction disorder of the heart Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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MYH6-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2024

The MYH6 c.5476_5477delinsAA variant is predicted to result in an in-frame deletion and insertion. This variant was reported in unrelated individuals with dilated or hypertrophic cardiomyopathy (Carniel et al. 2005. PubMed ID: 15998695; described as p.Gly1826Ser and p.Gly1826Asp as a complex genotype in Table S4, Lopes et al. 2013. PubMed ID: 23396983; described as p.Asp1826Asn, Hershberger et al. 2010. PubMed ID: 20215591; Kim et al. 2020. PubMed ID: 32492895; Cowan et al. 2020. PubMed ID: 32603605). This variant, along with a second MYH6 variant, was also detected in an individual with hypertrophic cardiomyopathy (Cecconi et al. 2016. PubMed ID: 27600940). In gnomAD, the c.5476_5477delinsAA variant appears as two separate allele calls (c.5476G>A and c.5477G>A), and the two variants are documented to occur in cis (on the same allele) in over fifty heterozygous individuals (https://gnomad.broadinstitute.org/variant/14-23853739-CC-TT?dataset=gnomad_r2_1). At this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2023

Reported in association with cardiomyopathy in published literature, although some patients harbor additional cardiogenetic variants (also described as c.25743_25744delGGinsAA due to alternative nomenclature; Hershberger et al., 2010; Cecconi et al., 2016; Cowan et al., 2020); Identified in a patient with non-syndromic congenital heart disease (CHD) (Pulignani et al., 2018); In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27600940, 15998695, 22337857, 23396983, 32492895, 20215591, 32603605, 29332214) -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 23, 2019

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Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878854502; hg19: chr14-23853739;