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_000257.4(MYH7):c.2678C>A (p.Ala893Glu)

CA012807

164319 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: cde5b340-3850-40d7-88c2-b19d406c169f
Approved on: 2021-03-10
Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.2678C>A
NM_000257.4(MYH7):c.2678C>A (p.Ala893Glu)
ENST00000355349.4:c.2678C>A
ENST00000355349.3:c.2678C>A
NM_000257.3:c.2678C>A
NC_000014.9:g.23424770G>T
CM000676.2:g.23424770G>T
NC_000014.8:g.23893979G>T
CM000676.1:g.23893979G>T
NC_000014.7:g.22963819G>T
NG_007884.1:g.15892C>A

Uncertain Significance

Met criteria codes 3
PM2 PM1 PS4_Supporting
Not Met criteria codes 23
PP1 PP3 PP4 PP2 PS3 PM5 PM4 PM6 PM3 PS1 PS2 BA1 PVS1 BP3 BP1 BP7 BP5 BP2 BP4 BS4 BS3 BS1 BS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The NM_000257.4(MYH7):c.2678C>A (p.Ala893Glu) variant has been reported in 3 individuals with HCM (PS4_Supporting; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.) and segregated with HCM in 2 relatives from 2 families (GeneDx pers. comm.; LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. 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_Supporting, PM2, PM1.
Met criteria codes
PM2
Absent from gnomAD with good coverage (~30x genomes and ~70x exomes)
PM1
Located in MYH7 head domain
PS4_Supporting
Variant reported in 3 cases of HCM (GeneDx, Invitae, and LMM). Since conflicting information received from BluePrint. Now counting. NOTE FROM CURATOR: Third patient reported in Clinvar by Blueprint Genetics but condition not provided, after contacting then they indicated the variant was de novo in a patient with HCM onset between the age of 10-20. MAK RESPONSE FROM BLUEPRINT (EMAIL on 3/3/21): "We have seen at least one patient with this variant who presented with severe obstructive hypertrophic cardiomyopathy in early childhood requiring cardiac transplant. We did not do any familial testing in our laboratory (that we were aware of), however, by history, an affected sibling had the same variant. The patient was tested with the Comprehensive Cardiology Panel that now contains 254 genes (217 at the time the patient was tested minus the mitochondrial genome)."
Not Met criteria codes
PP1
2 segregations in 2 families (LMM and GeneDx)
PP3
Computational tools are borderline; REVEL does not support impact and variant is not conserved in multiple mammals (Thr & Ser).
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
PM1 applied, PP2 not applicable to MYH7 per Kelly et al. adapted ACMG criteria
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Multiple other changes within ClinVar: Changes to Thr and Ser are 1* VUS (not evaluated), while change to Val was conflicting (evaluated - reassessment) and is now proposed as VUS
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
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
PS2
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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