SHC1

Chr 1

SHC adaptor protein 1

Also known as: SHC, SHCA

NCBI Gene: 6464 ENSG00000160691 UniProt: P29353 OMIM: 600560

This gene encodes three main isoforms that differ in activities and subcellular location. While all three are adapter proteins in signal transduction pathways, the longest (p66Shc) may be involved in regulating life span and the effects of reactive oxygen species. The other two isoforms, p52Shc and p46Shc, link activated receptor tyrosine kinases to the Ras pathway by recruitment of the GRB2/SOS complex. p66Shc is not involved in Ras activation. Unlike the other two isoforms, p46Shc is targeted to the mitochondrial matrix. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.65

Clinical Summary— SHC1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 65 VUS of 97 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.002

Z-score 2.87

OE 0.37 (0.22–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.33Z-score

OE missense 0.80 (0.73–0.89)

289 obs / 359.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.22–0.65)

0≤0.351.4

Missense OE?0.80 (0.73–0.89)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 9 / 24.2Missense obs/exp: 289 / 359.8Syn Z: -0.37

This gene — mechanism propensity

0.6549th %ile

GOF

0.6638th %ile

LOF

0.4135th %ile

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

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

97 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS65

Likely Benign2

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	2	0	2
Likely Pathogenic	0	0	0
VUS	0	65	65
Likely Benign	0	2	2
Benign	0	0	0
Total	2	67	69

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap SHC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →