Variant: NM_000257.3(MYH7):c.3286G>T (p.Asp1096Tyr)

CA013546

42953 (ClinVar)

Gene: MYH7

Condition: cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 8b156efb-afd3-4dd9-9602-39a13d32a5b6

HGVS expressions

NM_000257.3:c.3286G>T
NM_000257.3(MYH7):c.3286G>T (p.Asp1096Tyr)
NC_000014.9:g.23421008C>A
CM000676.2:g.23421008C>A
NC_000014.8:g.23890217C>A
CM000676.1:g.23890217C>A
NC_000014.7:g.22960057C>A
NG_007884.1:g.19654G>T
ENST00000355349.4:c.3286G>T
ENST00000355349.3:c.3286G>T
NM_000257.4:c.3286G>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BS1 PP3

• Not Met criteria codes: PM2 PS4

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.3286G>T (p.Asp1096Tyr) variant in MYH7 has been identified in 0.023% (FAF 95% CI; 40/129162) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3, BS1

Met criteria codes

• BS1: has been identified in 0.023% (FAF 95% CI; 40/129162) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; PMID:29300372).
• PP3: Tools predict damaging

Not Met criteria codes

• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: 4 probands with HCM (including SHaRe and ClinVar SCV000256636.2) however PS4 not applied since PM2 not met

Approved on: 2021-03-22

Published on: 2021-08-25