Evidence Repository - Clinical Genome Resources

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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Variant: NM_000257.4(MYH7):c.3578G>A (p.Arg1193His)

CA013815

42965 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: da44d8c5-f133-4882-8a5a-1a6c85b2e7b3

Approved on: 2021-12-22

Published on: 2021-12-22

HGVS expressions

NM_000257.4:c.3578G>A

NM_000257.4(MYH7):c.3578G>A (p.Arg1193His)

NC_000014.9:g.23419993C>T

CM000676.2:g.23419993C>T

NC_000014.8:g.23889202C>T

CM000676.1:g.23889202C>T

NC_000014.7:g.22959042C>T

NG_007884.1:g.20669G>A

ENST00000355349.4:c.3578G>A

ENST00000355349.3:c.3578G>A

NM_000257.3:c.3578G>A

Likely Pathogenic

PP1_Moderate PS4_Moderate PP3 PM2

BS2 BS3 BS4 BS1 BP3 BP1 BP7 BP5 BP2 BP4 PS1 PS2 PS3 PP4 PP2 BA1 PM1 PM4 PM5 PM6 PVS1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) variant has been identified in at least 9 individuals with DCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 1 individual with DCM and a bicuspid aortic valve (PS4_Moderate; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 5 affected relatives with DCM from 4 families (PP1_Moderate; LMM pers. comm.; OMGL pers. comm.). Additionally, this variant has also been reported in 1 individual with LVNC, 1 individual with non-ischemic cardiomyopathy and 1 individual with biventricular dilation with ventricular tachycardia (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2, PP3.

PP1_Moderate

5 seg w DCM 4 families (4 LMM, from 3 families, 1 OMGL )

PS4_Moderate

This variant is only reported in 9 DCM probands (2 GeneDx, 6 LMM, 1 OMGL).Also 1 LVNC (Genedx), 1 non-ischemic CM (Invitae), 1 Biventricular dilation with VT(LMM)

PP3

In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function

PM2

Allele frequency = 0.001% in gnomAD. (europeans)

BS2

This information is not available in the literature or population databases.

BS3

Functional Data is not available in the literature for this variant.

BS4

Evidence for lack of segregation not reported in the literature or by ClinGen laboratories in the Internal Data Log,

BS1

Allele frequency = 0.001% in gnomAD. (europeans)

BP3

This is a missense variant.

BP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP7

This is a missense variant.

BP5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP2

This information is not available in the literature.

BP4

In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function

PS1

2 other variants at same codon do not meet criteria for pathogenicity

PS2

This information is not available in the literature.

PS3

Functional Data is not available in the literature for this variant.

PP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BA1

Allele frequency = 0.0008% in gnomAD.

PM1

not in head domain

PM4

This is a missense variant.

PM5

2 other variants at same codon do not meet criteria for pathogenicity

PM6

This information is not available in the literature.

PVS1

This is a missense variant.

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