NM_000257.4(MYH7):c.958G>A (p.Val320Met) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Aug 6, 2012)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000223879.1

Allele description [Variation Report for NM_000257.4(MYH7):c.958G>A (p.Val320Met)]

NM_000257.4(MYH7):c.958G>A (p.Val320Met)

Gene:
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q11.2
Genomic location:
Preferred name:
NM_000257.4(MYH7):c.958G>A (p.Val320Met)
Other names:
p.V320M:GTG>ATG
HGVS:
  • NC_000014.9:g.23430601C>T
  • NG_007884.1:g.10061G>A
  • NM_000257.4:c.958G>AMANE SELECT
  • NP_000248.2:p.Val320Met
  • LRG_384t1:c.958G>A
  • LRG_384:g.10061G>A
  • NC_000014.8:g.23899810C>T
  • NM_000257.2:c.958G>A
  • NM_000257.3:c.958G>A
  • P12883:p.Val320Met
Protein change:
V320M
Links:
UniProtKB: P12883#VAR_020803; dbSNP: rs376897125
NCBI 1000 Genomes Browser:
rs376897125
Molecular consequence:
  • NM_000257.4:c.958G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
11

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000280360Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Aug 6, 2012)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providednot providedclinical testing

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280360.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided11not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val320Met (c.958 G>A) in the MYH7 gene. We re-reviewed these results on 6/27/2012 and again on 10/1/13 and February 9th, 2015. Based on the strong case data and very low frequency in the general population, we consider this variant likely disease causing. The variant has been seen in at least 10 unrelated cases of HCM (not including this patient). There is weak segregation data. Havndrup et al (2003) observed this variant in a Danish woman with HCM (likely the same case that was included in Ho et al 2009). Her 15yo daughter had a proximal 'septal bulb' and also carried the variant. Fokstuen et al (2011) observed the variant in one patient with HCM recruited from Europe (not Denmark). Santos et al (2012) reported the variant in one patient with HCM in their Portugese cohort. We have seen this variant in one other HCM patient in our cohort. She had 12 HCM genes sequenced at PGxHealth/Familion and only this variant was found. Marsiglia et al (2013) sequenced MYH7, MYBPC3, TNNT2 in 268 Brazilian patients with HCM and found the variant in 5 patients. Alvarez-Acosta et al (2014) reported the variant in 1 of 124 HCM patients recruited from a clinic in Spain. It isn't entirely clear but it looks like the patient underwent sequencing of MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL2, MYL3, TNNC1. The patient also had a variant in MYL2. He had a relatively severe phenotyped, diagnosed at 16yo, with atrial fibrillation, 2.6 cm wall thickness, syncope, left ventricular outflow tract obstruction, heart failure, LBBB, ICD, and underwent alcohol ablation. His first cousin carried only the MYL2 variant and also had HCM. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The valine at codon 320 is completely conserved across species, though not all neighboring amino acids are. I could not find any other variants reported in association with disease at this codon, though there are a few at nearby codons (p.Phe312Cys, p.Ala326Pro). In total the variant has been seen in ~1-4/60,452 published controls, laboratory controls, and publicly available population datasets. The variant was reported online in 2 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 10/1/13). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Of note, variants with strong evidence for pathogenicity have been observed at similar low frequencies in this data set. The variant was reported online in 1 of 59,906 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 9th, 2015). Specifically, the variant was observed in 1 individual of African descent. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Of note, the ESP and ExAC databases overlap (ExAC includes ESP). The discrepancy between them may be attributable to the primary data being re-analyzed in ExAC. The Seidman group observed the variant in 2 of 1963 individuals from the Jackson Heart Study who underwent sequencing of eight sarcomere genes (Bick et al 2012). They note the following about those individuals phenotypes: a 41yo with left ventricular wall thickness of 1 cm, LVDD of 4.2, LAD of 3.83, and FS of 0.38 and no known physiological risk factors; a 63yo with LVWT 1.02 cm, LVDD 4.54, LAD 3.69, FS 0.43 and no known physiological risk factors. The Jackson Heart Study is included in ExAC. The variant was not observed in the following published control samples: 100 Danish individuals (Havndrup et al 2003), 246 German and Italy individuals with normal echocardiograms and a mean age of 71 years (Fokstuen et al 2011). PGxHealth/Familion reported in another patient's report that they have not seen this variant in 200 controls of varying ancestry.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided11not providednot providednot provided

Last Updated: Nov 27, 2021

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