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.2804A>T (p.Glu935Val)

CA013125

181207 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d209f979-a788-4850-8e51-868dda661acc

HGVS expressions

NM_000257.4:c.2804A>T
NM_000257.4(MYH7):c.2804A>T (p.Glu935Val)
ENST00000355349.4:c.2804A>T
ENST00000355349.3:c.2804A>T
NM_000257.3:c.2804A>T
NC_000014.9:g.23424025T>A
CM000676.2:g.23424025T>A
NC_000014.8:g.23893234T>A
CM000676.1:g.23893234T>A
NC_000014.7:g.22963074T>A
NG_007884.1:g.16637A>T

Uncertain Significance

Met criteria codes 3
PM1 PM2 PP3
Not Met criteria codes 17
PM6 PS3 PM4 PM5 PS2 PS4 PS1 BA1 PVS1 BP5 BP2 BP7 BP4 BS4 BS3 BS1 PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.2804A>T (p.Glu935Val) variant in MYH7 has been identified in at least 1 individual with early-onset HCM (<25 yo) who also carried a second MYH7 variant (Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940). Due to the potential overlap in these cohorts and the presence of a second variant, the PS4_Supporting criterion is not met. This variant was also identified in 0.0003% (FAF 95% CI; 2/113768) of non-Finnish European chromosomes in gnomAD v2.1.1 (PM2; https://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 disease-associated (PM1; Walsh 2017 PMID:27532257). 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): PM2; PM1; PP3
Met criteria codes
PM1
missense variant in the head domain
PM2
This variant was identified in 0.0003% (FAF 95% CI; 2/113768) of non-Finnish European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org/).
PP3
Align GVGD: C25, SIFT: deleterious, MutationTaster: disease causing, PolyPhen-2: probably damaging. REVEL: 0.903 (generally consistent, suggestive of pathogenicity). highly conserved amino acid (Glu: 92 species, Asp: 3 species), highly conserved nucleotide, moderate physicochemical difference (121). No significant splicing impact
Not Met criteria codes
PM6
no de novo occurrences
PS3
none
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
E935K meets criteria for for likely pathogenic (PM2, PS4_supporting, PM1, PP3), therefore cannot be used for PM5 (can only use pathogenic variants)
PS2
no de novo occurrences
PS4
GeneDx and Genomic Research Center, Shahid Beheshti University of Medical Sciences report that they have detected this variant in ClinVar, however there is limited clinical information and no proband counts. Given this, plus the 2 samples reported in the literature (note that both pieces of literature are from Italy and there is author overlap, so could be overlap in patients), >2 probands is likely, but don't have specific data to support used of rule. Not applying rule due to potential overlap in literature counts and presence of other MYH7 variant (c.3973G>A, p.Ala1325Thr) in that same literature report (Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940)
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
PVS1
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
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
BS4
No segregation data
BS3
none
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No segregation data
Approved on: 2021-06-16
Published on: 2021-06-16
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