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.964T>A (p.Ser322Thr)

CA017009

181330 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 62e89a88-728e-473b-91db-c4f99f2fac8f
Approved on: 2021-04-21
Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.964T>A
NM_000257.4(MYH7):c.964T>A (p.Ser322Thr)
NC_000014.9:g.23430595A>T
CM000676.2:g.23430595A>T
NC_000014.8:g.23899804A>T
CM000676.1:g.23899804A>T
NC_000014.7:g.22969644A>T
NG_007884.1:g.10067T>A
ENST00000355349.4:c.964T>A
ENST00000355349.3:c.964T>A
NM_000257.3:c.964T>A

Uncertain Significance

Met criteria codes 3
PS4_Supporting PM1 PM2
Not Met criteria codes 19
BP5 BP2 BP4 BP1 PS2 PS1 PS3 PP4 PP2 PP1 PP3 PM3 PM6 PM5 BA1 BS2 BS4 BS3 BS1

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.964T>A (p.Ser322Thr) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. 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, PM1.
Met criteria codes
PS4_Supporting
This variant has been classified by two laboratories in Clinvar as a VUS. These are reflected in the internal data log, with 1x HCM proband from Invitae and 1xHCM proband from GeneDx. This variant has been reported in one publication in a proband with HCM (Walsh 2017 PMID:27532257), based on the source of the cohort appears to be an additional proband count. This gives a total of 3 proband with HCM identified to have this variant, sufficient to apply PS4 as supporting criteria No additional literature found in ClinVar, Google, or other searches.
PM1
Located in MYH7 head domain
PM2
Variant is absent from population databases with good coverage in gnomAD
Not Met criteria codes
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
Not applicable to MYH7
PP1
No segregation data available
PP3
In silico predictions are mixed, insufficient to apply PP3
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No other variants at this codon in ClinVar
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
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
BS3
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
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