SHOC2

Chr 10AD

SHOC2 leucine rich repeat scaffold protein

Also known as: NSLH1, SIAA0862, SOC2, SUR8

NCBI Gene: 8036 ENSG00000108061 UniProt: Q9UQ13 OMIM: 602775

The protein functions as a scaffolding component of the SHOC2-MRAS-PP1c complex that regulates MAPK pathway activation by dephosphorylating inhibitory sites on RAF kinases. Mutations cause Noonan syndrome-like with loose anagen hair 1, an autosomal dominant condition affecting growth, development, cardiac function, and hair structure. The gene is highly constrained against loss-of-function variants in the population, indicating that functional copies are essential for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.141 OMIM phenotype

VCEP Guidelines: RASopathyReleased

View Specifications ClinGen Panel

Clinical Summary— SHOC2

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Gene-Disease Validity (ClinGen)

Noonan syndrome-like disorder with loose anagen hair · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 348 VUS of 718 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.14LOEUF

pLI 0.999

Z-score 4.31

OE 0.00 (0.00–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.97Z-score

OE missense 0.52 (0.45–0.59)

153 obs / 296.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.14)

0≤0.351.4

Missense OE?0.52 (0.45–0.59)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 0 / 21.7Missense obs/exp: 153 / 296.8Syn Z: 0.80

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSHOC2-related Noonan-like syndrome with loose anagen hairGOFAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.3887th %ile

LOF

0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.14

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFA recurrent activating mutation in SHOC2 (p.Ser2Gly) causes Mazzanti syndrome, a RASopathy characterized by features resembling Noonan syndrome and distinctive ectodermal abnormalities.1

LOFThis is might be the first report suggesting that haploinsufficiency of SHOC2 can result in a RASopathy-like phenotype.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

718 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS348

Likely Benign295

Benign36

Conflicting28

Pathogenic

Likely Pathogenic

348

VUS

295

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	2	0	0	2
VUS	10	307	29	2	348
Likely Benign	0	6	93	196	295
Benign	0	2	29	5	36
Conflicting	—				28
Total	10	321	151	203	713

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap SHOC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →