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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.341T>C (p.Ile114Thr)

CA013685

181300 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2a1f9856-ae11-4238-a6f1-2892ad8db5f8
Approved on: 2021-03-31
Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.341T>C
NM_000257.4(MYH7):c.341T>C (p.Ile114Thr)
NC_000014.9:g.23433088A>G
CM000676.2:g.23433088A>G
NC_000014.8:g.23902297A>G
CM000676.1:g.23902297A>G
NC_000014.7:g.22972137A>G
NG_007884.1:g.7574T>C
ENST00000355349.4:c.341T>C
ENST00000355349.3:c.341T>C
NM_000257.3:c.341T>C
More

Uncertain Significance

Met criteria codes 3
PP3 PS4_Supporting PM2
Not Met criteria codes 12
PP1 PM6 PM5 PM1 BA1 BS4 BS3 BS1 BP4 PS3 PS2 PS1

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.341T>C (p.Ile114Thr) variant has been identified in 4 individuals with HCM (PS4_Supporting; Restrepo-Cordoba 2017 PMID:28138913; GeneDx pers. comm.; Invitae pers. comm.). This variant has also been identified in 1 individual with DCM who also carried a truncating variant in TTN and an individual with heart disease and sensory disfunction (Ambry pers. comm.; LMM pers. comm.). This variant was identified in 0.0009% (1/113612) of European chromosomes by 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, 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, PP3.
Met criteria codes
PP3
REVEL meta-predictor score is 0.896, above 0.75 threshold. Multiple predictors predict the variant is deleterious.
PS4_Supporting
4 HCM probands - 1 each from PMID: 28138913 and Invitae, and 2 from GeneDx 1 proband with DCM with TTN tv and 1 complex phenotype from Ambry No additional literature hits in ClinVar or Google Scholar.
PM2
Subpopulation with highest frequency in gnomAD: 1/113612 for European (non-Finnish)
Not Met criteria codes
PP1
No segregation data in literature or from internal data log
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
NM_000257.4(MYH7):c.341T>A (p.Ile114Asn) also in ClinVar, but listed as 1* VUS
PM1
Not in the mutational hotspot of p.181-937
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No segregation data in literature or from internal data log
BS3
No functional evidence in the literature
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
PS3
No functional evidence in the literature
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
Curation History
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