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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000257.4(MYH7):c.4210G>A (p.Val1404Met)

CA014652

42999 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1ae35f84-d13b-4f95-9579-2e1a9fbbf0b6

HGVS expressions

NM_000257.4:c.4210G>A

NM_000257.4(MYH7):c.4210G>A (p.Val1404Met)

ENST00000355349.4:c.4210G>A

ENST00000355349.3:c.4210G>A

NM_000257.3:c.4210G>A

NC_000014.9:g.23417646C>T

CM000676.2:g.23417646C>T

NC_000014.8:g.23886855C>T

CM000676.1:g.23886855C>T

NC_000014.7:g.22956695C>T

NG_007884.1:g.23016G>A

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

PM6 PM1 PM5 PM2 PS2 PS1 PS4 BA1 BP4 BS4 BS1 PP3 PP1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.4210G>A (p.Val1404Met) variant in MYH7 has been identified in 3 individuals with HCM (Wang 2014 PMID:25132132; Invitae pers. comm.) and also segregated in 1 affected relative with HCM (Invitae pers. comm.); however this data is currently insufficient to apply PP1. Of note, 1 of the 2 affected individuals from Invitae also carried a splice variant in MYBPC3 and was in their mid 20s at the time of testing. This variant was identified in 0.004% (FAF 95% CI; 9/129152) of European chromosomes by gnomAD v2.1.1 (http://gnomad.broadinstitute.org). 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). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): none.

PM6

No de novo evidence

PM1

Variant is outside of hotspot domain

PM5

No other variants at same codon in ClinVar or HGMD

PM2

0.004% (FAF; 9/129152) of European. frequency just at threshold

PS2

No de novo evidence

PS1

No other variants at same codon in ClinVar or HGMD

PS4

3 patients total. 2 unrelated HCM patients tested at Invitae. One HCM patient in 25132132. This variant has been identified in 3 individuals with HCM (Wang 2014 PMID:25132132; Invitae: pers comm) and segregated in 1 affected relative with HCM (Invitae: pers comm). One of the 2 affected individuals from Invitae also carried a pathogenic splice variant in MYBPC3 and was in his/her mid 20s at the time of testing. 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

BA1

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 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

PP3

REVEL is >0.75, but other tools are mixed. PP3 not met.

PP1

Variant found in HCM patient's relative who also had HCM, tested at Invitae. Also found in relative who did not have HCM

Approved on: 2021-06-16

Published on: 2021-06-16

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