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]
x This classification has been retracted/unpublished!
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • 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
Approved on: 2021-03-22
Published on: 2021-10-13

HGVS expressions

NM_000257.3:c.5726G>C
NM_000257.3(MYH7):c.5726G>C (p.Arg1909Pro)
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
ENST00000355349.4:c.5726G>C
ENST00000355349.3:c.5726G>C
NM_000257.4:c.5726G>C
More

Likely Pathogenic

Met criteria codes 3
PP3 PM2 PM6
Not Met criteria codes 10
PP1 BA1 BS1 BS4 BS3 BP4 PS1 PS4 PS2 PS3

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
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.
PM2
Absent with >30x coverage
PM6
LMM: Assumed de novo occurrence in case with DCM and myopathy (SCV000059632)
Not Met criteria codes
PP1
LMM: Variant segregated with disease in 2 affected family members (ClinVar SCV000059632) - currently insufficient for PP1
BA1
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No functional data
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
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.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No functional data
Curation History
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