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.1193G>A (p.Gly398Glu)

CA010341

180434 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 0b401d72-9fbc-4cf9-a2ef-5d85b2e671ed
Approved on: 2021-10-01
Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.1193G>A
NM_000257.4(MYH7):c.1193G>A (p.Gly398Glu)
NC_000014.9:g.23429293C>T
CM000676.2:g.23429293C>T
NC_000014.8:g.23898502C>T
CM000676.1:g.23898502C>T
NC_000014.7:g.22968342C>T
NG_007884.1:g.11369G>A
ENST00000355349.4:c.1193G>A
ENST00000355349.3:c.1193G>A
NM_000257.3:c.1193G>A

Uncertain Significance

Met criteria codes 1
PM1
Not Met criteria codes 21
BS4 BS1 BS3 BS2 BP7 BP4 BP1 BP3 PVS1 PS4 PS2 PS1 BA1 PS3 PP1 PP3 PP2 PM6 PM5 PM4 PM2

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.1193G>A (p.Gly398Glu) variant has been identified in at least 4 individuals with HCM (Olivotto 2008 PMID:18533079; Homburger 2016 PMID:27247428; Invitae pers. comm.). This variant has been identified in 0.00524% (FAF 95% CI; 3/15414) of European chromosomes in genomes only by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is too high to apply PM2. However, this represents only a fraction of the total European chromosomes, suggesting low coverage at this locus. Therefore, data from large population studies are insufficient to assess the frequency of this variant. Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). 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): PM1
Met criteria codes
PM1
Missense variant in residue 181-937
Not Met criteria codes
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
BS3
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
BP7
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
BP1
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Observed in 2-5 probands. Observed in 1 patient in Olivotto et al, PMID 18533079 Observed in 3 probands in Homburger et al, PMID 27247428 ClinVar entry: claims variant has been detected in HCM-affected individual(s), but does not specify how many individual(s) SHaRe registry used Invitae in some instances, so could be duplicate. Variant has been identified in at least 4 individuals with HCM (PS4_Supporting; Olivotto 2008 PMID:18533079; Homburger 2016 PMID:27247428; Invitae pers. comm.). PS4 not applied as PM2 is not met,
PS2
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL score is borderline at 0.77, variant is not conserved lower mammals and birds, some tools do not predict impact.
PP2
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
Genomes only, but good coverage in exomes so unclear why not present or not called. This variant has been identified in 0.00524% (FAF 95% CI; 3/15414) of European (non-Finnish) chromosomes in genomes only by gnomAD v2.1.1 (https://gnomad.broadinstitute.org).
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