Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000257.3(MYH7):c.5302G>A (p.Glu1768Lys)

CA015893

43059 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1f7adfd4-301c-4b88-bb44-5784d44ef5ce
Approved on: 2021-03-22
Published on: 2021-08-25

HGVS expressions

NM_000257.3:c.5302G>A
NM_000257.3(MYH7):c.5302G>A (p.Glu1768Lys)
NC_000014.9:g.23415252C>T
CM000676.2:g.23415252C>T
NC_000014.8:g.23884461C>T
CM000676.1:g.23884461C>T
NC_000014.7:g.22954301C>T
NG_007884.1:g.25410G>A
ENST00000355349.4:c.5302G>A
ENST00000355349.3:c.5302G>A
NM_000257.4:c.5302G>A

Uncertain Significance

Met criteria codes 3
PS4_Moderate PP3 PM2
Not Met criteria codes 8
BS3 BS1 BP4 PS1 PS3 BA1 PM1 PM5

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.5302G>A (p.Glu1768Lys) variant in MYH7 has been identified in at least 7 individuals with HCM (PS4_Moderate; Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Murphy 2016 PMID:26914223; Berge 2014 PMID:24111713; Homburger 2016 PMID:27247418; Cecconi 2016 PMID:27600940; LMM SCV000059606.5). In vitro studies showed this variant had a slight effect on protein structure, but no effect on the ability to incorporate into muscle sarcomeres in an experimental system (Wolny 2013 PMID:24047955); however, this evidence is insufficient to apply PS3. Additionally this variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PP3
Met criteria codes
PS4_Moderate
This variant has been identified in at least 7 probands with HCM (Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Murphy 2016 PMID:26914223; Berge 2014 PMID:24111713; Homburger 2016 PMID:27247418; Cecconi 2016 PMID:27600940; LMM SCV000059606.5). LMM Internal - 1 Caucasian individual with HCM and in 1 affected relative with syncope (confirmed to not overlap with SHaRE cases. 2 proband with HCM (Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Murphy 2016 PMID:26914223) - All cohorts out of Mayo 1 proband with HCM (Berge 2014 PMID:24111713) 2 probands with HCM (SHaRe - tested at GeneDx; Homburger 2016 PMID:27247418) 1 proband with early onset HCM (Cecconi 2016 PMID:27600940)
Variant identified in 1 proband with HCM PubMed:15358028
PP3
All tools below predict damage
PM2
Absent from gnomAD with >30x coverage on genomes and ~100x coverage on genomes.
Not Met criteria codes
BS3
Authors investigated the impact of p.Glu1768Lys variant as a tail variant on its ability to incorporate into muscle sarcomeres in vivo. Using the adenoviral expression system, we expressed and characterized the p.Glu1768Lys variant in adult cardiomyocytes. When quantifying the proportions of cells with normal or limited incorporation, the eGFP MHC incorporation for this variant was similar to wild type. Conclusion was this variant had little effect on sarcomeric incorporation, but was associated with increased helical content in the 7H peptides. PubMed:24047955
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
In vitro studies showed variant had slight effect on protein structure, but no effect on the ability to incorporate into muscle sarcomeres in an experimental system (Wolny 2013 PMID: 24047955).
Authors investigated the impact of p.Glu1768Lys variant as a tail variant on its ability to incorporate into muscle sarcomeres in vivo. Using the adenoviral expression system, we expressed and characterized the p.Glu1768Lys variant in adult cardiomyocytes. When quantifying the proportions of cells with normal or limited incorporation, the eGFP MHC incorporation for this variant was similar to wild type. Conclusion was this variant had little effect on sarcomeric incorporation, but was associated with increased helical content in the 7H peptides. PubMed:24047955
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Variant is located outside the head domain
PM5
No other variants at this codon in ClinVar or HGMD
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