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.5726G>C (p.Arg1909Pro)

CA016422

43085 (ClinVar)

Gene: MYH7
Condition: dilated cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e0f90a49-fd56-4a6e-97a3-d0cc9611d193

HGVS expressions

NM_000257.3:c.5726G>C
NM_000257.3(MYH7):c.5726G>C (p.Arg1909Pro)
ENST00000355349.4:c.5726G>C
ENST00000355349.3:c.5726G>C
NM_000257.4:c.5726G>C
NC_000014.9:g.23413823C>G
CM000676.2:g.23413823C>G
NC_000014.8:g.23883032C>G
CM000676.1:g.23883032C>G
NC_000014.7:g.22952872C>G
NG_007884.1:g.26839G>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 3
PM6 PM2 PP3
Not Met criteria codes 10
BS3 BS4 BS1 BP4 PS4 PS1 PS2 PS3 BA1 PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.5726G>C (p.Arg1909Pro) variant in MYH7 has been reported as a de novo occurrence in 1 individual with dilated cardiomyopathy and myopathy features (PM6; Partners LMM ClinVar SCV000059632.5). Additionally, this variant reportedly segregated with DCM and in 2 affected relatives (Partners LMM ClinVar SCV000059632.5); however this data is currently insufficient to establish co-segregation and apply PP1. This variant was absent from large population studies (PM2; https://gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). This variant was previously classified as likely pathogenic for DCM by this expert panel (EP) based on clinical judgement; however, upon re-evaluation, the EP has deemed that uncertain significance was more appropriate based on the available evidence. In summary, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM6, PM2, PP3.
Met criteria codes
PM6
LMM: Assumed de novo occurrence in case with DCM and myopathy (SCV000059632)
PM2
Absent with >30x coverage
PP3
Alamut tools (SIFT, MutationTaster, and PolyPhen2) are supportive of damaging, while AlignGVGD is tolerated. Sarcomere polyphen calls Path. Amino acid is conserved across 100 vertebrates in UCSC with good alignments. REVEL score also is strongly supportive of damaging.
Not Met criteria codes
BS3
No functional data
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
PS4
SUMMARY: This variant has been reported as a de novo occurrence in 1 individual with dilated cardiomyopathy and myopathy features (PM6; Partners LMM ClinVar SCV000059632.5). Additionally, this variant reportedly segregated with disease in 2 affected family members (Partners LMM ClinVar SCV000059632.5). LMM: 1 de novo occurrence (parentage not confirmed) in 1 individuals with DCM and myopathy with additional segregation in 2 affected family members with XXX. Has NOT been observed by any other labs (Invitae, OMGL, Ingles, Ambry, ARUP, CHEO, GeneDx) Google Scholar search found Wang 2018 (PMID: 29687901) which lists this variant, but only cites occurrence in Dalin 2017 (PMID: 27886618), which appears to only reference the DCM case submitted by the VCEP in 2016 and does not contribute any new additional probands. No additional literature listed in HGMD.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No functional data
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
LMM: Variant segregated with disease in 2 affected family members (ClinVar SCV000059632) - currently insufficient for PP1
Approved on: 2021-03-22
Published on: 2021-10-13
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