Congenital myopathy

Gene: HRAS

Green List (high evidence)

Comment on list classification: There are at least six unrelated cases reported with monoallelic HRAS variants and congenital myopathy with excess of muscle spindles (CMEMS). Hence, this gene can be promoted to green rating in the next GMS update.

Created: 1 Jun 2026, 8:08 p.m. | Last Modified: 1 Jun 2026, 8:08 p.m.

Panel Version: 7.40

PMID:17412879 (2007) reported five unrelated infants (four previously reported cases and one new case) with congenital myopathy with excess of muscle spindles (CMEMS), hypertrophic cardiomyopathy and variable features resembling Noonan syndrome, of which four patients were identified with four different heterozygous HRAS variants. Two of these (p.Gly12Val and p.Gly12Ser) have previously been observed in patients with Costello syndrome and two other variants (p.Glu63Lys and p.Gln22Lys) are novel.

PMID:25070542 (2014) reported a 5-year-old female patient with an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. The patient was identified with a previously described heterozygous missense variant (p.Glu63Lys).

PMID:26001911 (2015) reported a male patient with Congenital myopathy with excess of muscle spindles that was identified with previously described p.Glu63Lys variant in HRAS gene in the heterozygous state. The patient died at 31 months of age after a cardiorespiratory arrest.

This patient has been associated with both Costello syndrome and Congenital myopathy with excess of muscle spindles (MIM #218040) in OMIM (records last accessed 01 June 2026) and in Gene2Phenotype (both with Definitive rating on DD and Skin panels).

Created: 1 Jun 2026, 8:05 p.m. | Last Modified: 1 Jun 2026, 8:05 p.m.

Panel Version: 7.36

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital myopathy with excess of muscle spindles, OMIM:218040; Costello syndrome, OMIM:218040; Costello syndrome, MONDO:0009026

Publications

• 17412879
• 25070542
• 26001911

Green List (high evidence)

congenital myopathy with excess muscle spindles; congenital weakness, hypotonia, arthrogryposis, atrial tachycardia, hypertrophic cardiomyopathy, and marked excess of muscle spindles on biopsy.

Created: 22 May 2026, 1:49 p.m. | Last Modified: 22 May 2026, 1:49 p.m.

Panel Version: 7.14

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Costello syndrome 218040; Congenital myopathy with excess of muscle spindles 218040

Publications

• 17412879
• 11150980

I don't know

Comment on list classification: No clear evidence for primary muscle weakness in the absence of other features (e.g. HCM / Rasopathy facial gestalt) to make inclusion appropriate. Also, muscle biopsy features not consistent with inclusion criteria.

Created: 6 Feb 2017, 9:24 a.m.

Above PMID contains 4 unrelated individuals with HRAS mutations who presented with significant hypotonia, however there were other features consistent with Costello syndrome inc. HOCM / dysmorphology. I cannot find clear evidence to suggest there is an isolated phenotype, distinct from Costello, that would be appropriate for use on a congenital myopathy panel.

Created: 30 Jan 2017, 4:52 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Costello syndrome 218040; Congenital myopathy with excess of muscle spindles 218040

Publications

• PMID 17412879