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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Variant: NM_000257.3(MYH7):c.5588G>A (p.Arg1863Gln)

CA016295

43076 (ClinVar)

Gene: MYH7
Condition: dilated cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d896763f-e05b-46ff-a7a2-fc8cdd418c75
Approved on: 2021-03-22
Published on: 2021-08-25

HGVS expressions

NM_000257.3:c.5588G>A
NM_000257.3(MYH7):c.5588G>A (p.Arg1863Gln)
ENST00000355349.4:c.5588G>A
ENST00000355349.3:c.5588G>A
NM_000257.4:c.5588G>A
NC_000014.9:g.23414074C>T
CM000676.2:g.23414074C>T
NC_000014.8:g.23883283C>T
CM000676.1:g.23883283C>T
NC_000014.7:g.22953123C>T
NG_007884.1:g.26588G>A

Uncertain Significance

Met criteria codes 3
PS4_Moderate PP3 PM2
Not Met criteria codes 13
BP4 BA1 PS3 PS2 PS1 PP2 PP1 PM6 PM1 PM5 BS3 BS4 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.5588G>A (p.Arg1863Gln) variant in MYH7 has been identified in 1 individual with familial DCM (Hershberger 2008 PMID:19412328) and 7 individuals with DCM from clinical testing laboratories (PS4_Moderate; PMID:19412328; Partners LMM ClinVar SCV000059623.5; Invitae ClinVar SCV000818269.1, pers. comm.; Ambry pers. comm.; CHEO ClinVar SCV000901909.1, pers. comm.; GeneDx ClinVar SCV000208646.4, pers. comm.). This variant was also identified in 0.00027% (FAF 95% CI; 2/129158) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for dilated 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
SUMMARY: This variant has been identified in Literature: 8 probands with DCM (PS4_Moderate; PMID:19412328; Partners LMM ClinVar SCV000059623.5; Invitae ClinVar SCV000818269.1, pers. comm.; Ambry pers. comm.; CHEO ClinVar SCV000901909.1, pers. comm.; GeneDx ClinVar SCV000208646.4, pers. comm.) INDIVIDUAL DATA: Literature: 1 proband with DCM (PMID:19412328) LMM: 1 proband with DCM (Partners LMM ClinVar SCV000059623.5) Invitae: 1 proband with DCM (Invitae ClinVar SCV000818269.1, pers. comm.) Ambry: 1 proband with DCM (Ambry pers. comm.) CHEO: 1 proband with DCM (CHEO ClinVar SCV000901909.1, pers. comm.) GeneDx: Maybe 3 probands with DCM, 1 without other variants and 2 with other VUSs (GeneDx ClinVar SCV000208646.4, pers. comm.) Hershberger 2008 PMID:19412328 - 1 proband with familial DCM Andreasen 2013 PMID:23299917 - No proband data, only reviewed variants seen in ESP and in other mutational databases Norton 2012 PMID:22337857 - No proband data, only reviewed variants seen in ESP and in other mutational databases Kumar 2013 PMID:23403236 - No proband data, only looked at variant for Baysian computational approach
Variant identified in 1 proband with DCM PubMed:19412328
PP3
Alamut tools (Align GVGD, SIFT, and MutationTaster) all predict damaging. Sarcomere polyphen is Path. Conserved in all other available species, except for pacific walrus, which may represent alignment issues.
PM2
This variant was identified in 0.00027% (FAF 95% CI; 2/129158) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org).
Not Met criteria codes
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No functional data
PS2
No de novo data
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No segregation data
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Variant is located outside of the head domain (aa 181-937)
PM5
One other variant at same codon report (c.5587C>T p.Arg1863Trp) reported in HGMD. Only listed as in 1 proband in Walsh 2017 (PMID 27532257). Did not evaluate further.
BS3
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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